Selective androgen receptor degrader (sard) ligands and methods of use thereof

ABSTRACT

This invention provides novel indole, indazole, benzimidazole, benzotriazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating hyperproliferations of the prostate including pre-malignancies and benign prostatic hyperplasia, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, other AR-expressing cancers, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy&#39;s disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels (through degradation) and/or activity (through inhibition) of any androgen receptor including androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application from U.S. applicationSer. No. 16/556,828 filed on Aug. 30, 2019, which is a Continuationapplication from U.S. application Ser. No. 15/981,636 filed on May 16,2018, which is a Continuation-in-Part application from U.S. applicationSer. No. 15/331,777, filed on Oct. 21, 2016, which is aContinuation-in-Part application from U.S. application Ser. No.15/222,734 filed Jul. 28, 2016, which is a Continuation-in-Partapplication from U.S. application Ser. No. 15/135,334 filed Apr. 21,2016 which claims the benefit of U.S. Provisional Application Ser. No.62/150,763, filed on Apr. 21, 2015, U.S. Provisional Application Ser.No. 62/220,057, filed Sep. 17, 2015, U.S. Provisional Application Ser.No. 62/241,532, filed on Oct. 14, 2015, U.S. Provisional ApplicationSer. No. 62/220,187, filed on Sep. 17, 2015, and U.S. ProvisionalApplication Ser. No. 62/219,859, filed on Sep. 17, 2015 which areincorporated in their entirety herein by reference.

FIELD OF THE INVENTION

This invention is directed to novel indole, indazole, benzimidazole,benzotriazole, indoline, quinolone, isoquinoline, and carbazoleselective androgen receptor degrader (SARD) compounds, pharmaceuticalcompositions and uses thereof in treating hyperproliferations of theprostate including pre-malignancies and benign prostatic hypertrophy,prostate cancer, advanced prostate cancer, castration resistant prostatecancer, other AR-expressing cancers, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateralsclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids,and to methods for reducing the levels (through degradation) and/oractivity (through inhibition) of any androgen receptor includingandrogen receptor-full length (AR-FL) including pathogenic and/orresistance mutations, AR-splice variants (AR-SV), and pathogenicpolyglutamine (polyQ) polymorphisms of AR in a subject.

BACKGROUND OF THE INVENTION

Prostate cancer (PCa) is one of the most frequently diagnosednoncutaneous cancers among men in the US and is the second most commoncause of cancer deaths with more than 200,000 new cases and over 30,000deaths each year in the United States. PCa therapeutics market isgrowing at an annual rate of 15-20% globally.

Androgen-deprivation therapy (ADT) is the standard of treatment foradvanced PCa. Patients with advanced prostate cancer undergo ADT, eitherby luteinizing hormone releasing hormone (LHRH) agonists, LHRHantagonists or by bilateral orchidectomy. Despite initial response toADT, disease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). Up to 30% of patients withprostate cancer that undergo primary treatment by radiation or surgerywill develop metastatic disease within 10 years of the primarytreatment. Approximately 50,000 patients a year will develop metastaticdisease, which is termed metastatic CRPC (mCRPC).

Patients with CRPC have a median survival of 12-18 months. Thoughcastration-resistant, CRPC is still dependent on the androgen receptor(AR) signaling axis for continued growth. The primary reason for CRPCre-emergence is re-activation of AR by alternate mechanisms such as 1)intracrine androgen synthesis, 2) AR splice variants (AR-SV), e.g., thatlack ligand binding domain (LBD), 3) AR-LBD mutations with potential toresist AR antagonists (i.e., mutants that are not sensitive toinhibition by AR antagonists, and in some cases AR antagonists act asagonists of the AR bearing these LBD mutations); and 4) amplications ofthe AR gene within the tumor.

A critical barrier to progress in treating CRPC is that AR signalinginhibitors such as enzalutamide, flutamide, bicalutamide, andabiraterone, acting through the LBD, fail to inhibit growth driven bythe N-terminal domain (NTD)-dependent constitutively active AR-SV.Recent high-impact clinical trials with enzalutamide and abiraterone inCRPC patients demonstrated that 0% of AR-V7 (the predominant AR-SV)expressing patients responded to either of the treatments, indicatingthe requirement for next generation AR antagonists that target AR-SVs.In addition, a significant number of CRPC patients are becomingrefractory to abiraterone or enzalutamide, emphasizing the need for nextgeneration AR antagonists.

Current evidences demonstrate that CRPC growth is dependent onconstitutively active AR including AR-SV's that lack the LBD such asAR-V7 and therefore cannot be inhibited by conventional antagonists. ARinhibition and degradation through binding to a domain that is distinctfrom the AR LBD provides alternate strategies to manage CRPC.

Herein the NTD is biophysically characterized to interact with the SARDsof this invention via fluorescence polarization (FP), surface plasmonresonance (SPR), and NMR (Example 12). Biochemical evidence alsosupports the SARDs of this invention binding to a domain other than theLBD. E.g., SARDs of this invention degrade AR-SV in D567es cells lackingthe expression of any AR containing the LBD (Example 7). Further, the R-and S-isomers of the SARDs of this invention possess equipotent SARDactivity despite demonstrated differences in the binding and inhibitionof androgen-dependent transactivation via the LBD (Example 7, FIG. 42D).The report of SARD activity mediated through the NTD of AR is anunprecedented observation that may help explanation the prodigious ARantagonism profiles seen with the SARDs of this invention.

Molecules that degrade the AR prevent any inadvertent AR activationthrough growth factors or signaling pathways, or promiscuousligand-dependent AR activation. In addition, molecules that inhibit theconstitutive activation of AR-SVs are extremely important to provideextended benefit to CRPC patients.

Currently only a few chemotypes are known to degrade AR which includethe SARDs AZD-3514, ARN-509 and ASC-J9. However, these molecules degradeAR indirectly at much higher concentrations than their bindingcoefficient and they fail to degrade the AR-SVs that have become inrecent years the primary reason for resurgence of treatment-resistantCRPC.

This invention describes novel AR antagonists with unique pharmacologythat strongly (high potency and efficacy) and selectively bind AR(better than known antagonists), antagonize AR, and degrade AR fulllength (AR-FL) and AR-SV. Selective androgen receptor degrader (SARD)compounds possess dual degradation and AR-SV inhibitory functions andhence are distinct from any available CRPC therapeutics. These novelselective androgen receptor degrader (SARD) compounds inhibit the growthof PCa cells and tumors that are dependent on AR-FL and AR-SV forproliferation.

SARDs have the potential to evolve as new therapeutics to treat CRPCsthat are untreatable with any other antagonists. This unique property ofdegrading AR-SV has extremely important health consequences for prostatecancer. Till date only one synthetic molecule (EPI-001) and some marinenatural products such as sinkotamides and glycerol ether Napthetenone B,are reported to bind to AR-NTD and inhibit AR function and PCa cellgrowth, albeit at lower affinity and it has an inability to degrade thereceptor. The SARDs of this invention also bind AR-NTD and inhibitNTD-driven (e.g., ligand independent) AR activity.

The positive correlation between AR and PCa and the lack of a fail-safeAR antagonist, emphasizes the need for molecules that inhibit ARfunction through novel or alternate mechanisms and/or binding sites, andthat can elicit antagonistic activities within an altered cellularenvironment.

Although traditional antiandrogens such as enzalutamide, bicalutamideand flutamide and androgen deprivation therapies (ADT) were approved foruse in prostate cancer, there is significant evidence that antiandrogenscould also be used in a variety of other hormonal dependent and hormoneindependent cancers. For example, antiandrogens have been tested inbreast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7),non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9),partial androgen insensitivity syndrome (PAIS) associated malignanciessuch as gonadal tumors and seminoma, advanced pancreatic cancer (WorldJ. Gastroenterology 20(29):9229), cancer of the ovary, fallopian tubes,or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38:724-731; ADT was tested in AR-expressing recurrent/metastatic salivarygland cancers and was confirmed to have benefit on progression freesurvival and overall survival endpoints), bladder cancer (Oncotarget 6(30): 29860-29876; Int J. Endocrinol (2015), Article ID 384860),pancreatic cancer, lymphoma (including mantle cell), and hepatocellularcarcinoma. Use of a more potent antiandrogen such as a SARD in thesecancers may treat the progression of these and other cancers. Manyhormonal and non-hormonal cancers may benefit from SARD treatment suchas breast cancer, testicular cancer, cancers associated with partialandrogen insensitivity syndromes (PAIS) such as gonadal tumors andseminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubesor peritoneum, salivary gland cancer, bladder cancer, urogenital cancer,brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer,hepatocellular carcinoma, renal cancer, renal cell carcinoma,osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer,non-small cell lung cancer (NSCLC), gastric cancer, colon cancer,perianal adenoma, or central nervous system cancer.

Traditional antiandrogens such as bicalutamide and flutamide wereapproved for use in prostate cancer. Subsequent studies havedemonstrated the utility of antiandrogens (e.g., flutamide,spironolactone, cyproterone acetate, finasteride and chlormadinoneacetate) in androgen-dependent dermatological conditions such asandrogenic alopecia (male pattern baldness), acne vulgaris, andhirsutism. Prepubertal castration prevents sebum production andandrogenic alopecia but this can be reversed by use of testosterone,suggesting its androgen-dependence.

The AR gene has a polymorphism of glutamine repeats (polyQ) within exon1 which when shortened may augment AR transactivation (i.e.,hyperandrogenism). It has been found that shortened polyQ polymorphismsare more common in people with alopecia, hirsutism, and acne. Classicantiandrogens are undesirable for these purposes because they areineffective through dermal dosing and their long-term systemic useraises the risks of untoward sexual effects such as gynecomastia andimpotence. Further, similar to CRPC discussed above, inhibition ofligand-dependent AR activity alone may not be sufficient as AR can beactivated by various cellular factors other than the endogeneousandrogens testosterone (T) and dihydrotestosterone (DHT), such as growthfactors, kinases, co-activator overexpression and/or promiscuousactivation by other hormones (e.g., estrogens or glucocorticoids).Consequently, blocking the binding of T and DHT to AR with a classicalantiandrogen may not be sufficient to have the desired efficacy.

An emerging concept is the topical application of a SARD to destroy theAR local to the affected areas of the skin or other tissue(s) withoutexerting any systemic antiandrogenism. For this use, a SARD that doesnot penetrate the skin or is rapidly metabolized would be preferable.

Supporting this approach is the observation that cutaneous wound healinghas been demonstrated to be suppressed by androgens. Castration of miceaccelerates cutaneous wound healing while attenuating the inflammationin the wounds. The negative correlation between androgen levels andcutaneous healing and inflammation, in part, explains another mechanismby which high levels of endogenous androgens exacerbate hyperandrogenicdermatological conditions such those described herein. Further, itprovides a rationale for the treatment of wounds such as diabetic ulcersor even trauma, or skin disorders with an inflammatory component such asacne or psoriasis, with a topical SARD.

Androgenic alopecia occurs in ˜50% of Caucasian males by midlife and upto 90% by 80 years old. Minoxidil (a topical vasodilator) andfinasteride (a systemic 5-alpha reductase type II inhibitor) are FDAapproved for alopecia but require 4-12 months of treatment to produce atherapeutic effect and only arrest hair loss in most with mild tomoderate hair regrowth in 30-60%. Since currently available treatmentshave slow and limited efficacy that vary widely between individuals, andproduce unwanted sexual side effects, it is important to find a novelapproach to treat androgenic alopecia and other hyperandrogenicdermatologic diseases.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerativedisease. Patients with ALS are characterized by extended ARpolyglutamine repeats. Riluzole is an available drug for ALS treatment,however, only provides short-term effects. There is an urgent need fordrugs that extend the survival of ALS patients. Transgenic animals ofALS were shown to survive longer upon castration and reduction in ARlevels compared to castration+nandrolone (agonist) supplementation.Castration reduces the AR level, which may be the reason for extendedsurvival.

Uterine fibroids are common reproductive-age benign tumors thatcontribute to severe morbidity and infertility. Cumulative incidence is4 times higher in African-Americans compared to Caucasians andconstitutes a major health disparity challenge. Fibroids are the leadingindication for hysterectomy and their management averages $21 billionannually in the US. No long term minimally invasive therapies exist.Thus, promising drug therapies, with novel chemistry and pharmacologicalapproaches are needed to improve clinical efficacy. Androgens promoteuterine proliferation. Higher testosterone levels increase the risk ofuterine fibroids. Treatment of uterine fibroids with SARDs would helpprevent or treat uterine fibroids.

An abdominal aortic aneurysm (AAA) is an enlarged area in the lower partof the aorta, the major blood vessel that supplies blood to the body.The aorta, about the thickness of a garden hose, runs from your heartthrough the center of your chest and abdomen. Because the aorta is thebody's main supplier of blood, a ruptured abdominal aortic aneurysm cancause life-threatening bleeding. Depending on the size and the rate atwhich your abdominal aortic aneurysm is growing, treatment may vary fromwatchful waiting to emergency surgery. Once an abdominal aortic aneurysmis found, doctors will closely monitor it so that surgery can be plannedif it's necessary. Emergency surgery for a ruptured abdominal aorticaneurysm can be risky. AR blockade (pharmacologic or genetic) reducesAAA. Davis et al. (Davis J P, Salmon M, Pope N H, Lu G, Su G, Meher A,Ailawadi G, Upchurch G R Jr. J Vasc Surg (2016) 63(6):1602-1612) showedthat flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcinepancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% comparedto vehicle (121%). Further AR −/− mice showed attenuated AAA growth(64.4%) compared to wildtype (both treated with elastase).Correspondingly, administration of a SARD to a patient suffering from anAAA may help reverse, treat or delay progression of AAA to the pointwhere surgery is needed.

X-linked spinal-bulbar muscular atrophy (SBMA— also known as Kennedy'sdisease) is a muscular atrophy that arises from a defect in the androgenreceptor gene on the X chromosome. Proximal limb and bulbar muscleweakness results in physical limitations including dependence on awheelchair in some cases. The mutation results in a protractedpolyglutamine tract added to the N-terminal domain of the androgenreceptor (polyQ AR). Binding and activation of this lengthened polyQ ARby endogeneous androgens (testosterone and DHT) results in unfolding andnuclear translocation of the mutant androgen receptor. These steps arerequired for pathogenesis and result in partial loss of thetransactivation function (i.e., an androgen insensitivity) and a poorlyunderstood neuromuscular degeneration. Currently there are nodisease-modifying treatments but rather only symptom directedtreatments. Efforts to target the polyQ AR of Kennedy's disease as theproximal mediator of toxicity by harnessing cellular machinery topromote its degradation, i.e., through the use of a SARD, hold promisefor therapeutic intervention. Selective androgen receptor degraders suchas those reported herein bind to and degrade a variety of androgenreceptors (full length, splice variant, antiandrogen resistance mutants,and are likely to degrade polyQ AR polymorphisms as well), indicatingthat they are promising leads for treatment of SBMA.

Here we describe indole, indazole, benzimidazole, benzotriazole,indoline, quinolone, isoquinoline, and carbazole SARDs that bind to LBDand an alternate binding and degradation domain (BDD; located outsidethe LBD in the NTD), antagonize AR, and degrade AR thereby blockingligand-dependent and ligand-independent AR activities. This novelmechanism produces improved efficacy when dosed systemically (e.g., forprostate cancer) or topically (e.g., for dermatological diseases).

SUMMARY OF THE INVENTION

In one aspect, this invention provides a method of treating prostatecancer in a subject in need thereof, wherein said subject has ARoverexpressing prostate cancer, castration-resistant prostate cancer,castration-sensitive prostate cancer, AR-V7 expressing prostate cancer,or d567ES expressing prostate cancer, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I:

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula I(1):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, the SARD compound is represented by a compound offormula I(2):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, in the compounds of formulas I, I(1), and I(2), W₁,W₂, W₃, W₄, W₅, and W₆ are CH. In one embodiment, W₂ is N and W₁, W₃,W₄, W₅, and W₆ are CH. In another embodiment, W₃ is N and W₁, W₂, W₄,W₅, and W₆ are CH. In one embodiment, W₁ is N and W₂, W₃, W₄, W₅, W₆ areCH.

In one embodiment, the SARD compound is represented by the structure offormula III:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula I.

In one embodiment, in the compound of formulas I, I(1), I(2), and III, Qis H, NO₂, COR, alkyl, alkoxy, aryl, CN, CF₃, F, Cl, Br or I. In oneembodiment, Z is CN. In another embodiment, Y is Cl or CF₃.

In one embodiment, the SARD compound is represented by the structure ofthe following compounds:

indoles:

benzimidazoles:

pyrrolo-pyridine:

indazoles:

benzotriazoles:

In one embodiment, the castration-resistant prostate cancer in themethod of the invention is AR overexpressing castration-resistantprostate cancer, F876L mutation expressing castration-resistant prostatecancer, F876L_T877A double mutation expressing castration-resistantprostate cancer, AR-V7 expressing castration-resistant prostate cancer,d567ES expressing castration-resistant prostate cancer, and/orcastration-resistant prostate cancer characterized by intratumoralandrogen synthesis.

In one embodiment, the castration-sensitive prostate cancer in themethod of the invention is F876L mutation expressingcastration-sensitive prostate cancer, F876L_T877A double mutationcastration-sensitive prostate cancer, and/or castration-sensitiveprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, the treating of castration-sensitive prostate cancerin the method of the invention is conducted in a non-castrate setting,or as monotherapy, or when castration-sensitive prostate cancer tumor isresistant to enzalutamide, apalutamide, and/or abiraterone.

In one aspect, this invention provides a method of treating prostatecancer in a subject in need thereof, wherein said subject has ARoverexpressing prostate cancer, castration-resistant prostate cancer,castration-sensitive prostate cancer, AR-V7 expressing prostate cancer,or d567ES expressing prostate cancer, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂- alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula V(1):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and l are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by a compound offormula V(2):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and l are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula VI:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula IV:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, in the compounds of formulas V, V(1), V(2), VI, VII,and IV, Q is H, F, Cl, Br, I, NO₂, CN, and aryl.

In one embodiment, the SARD compound is represented by the followingstructures: indolines:

isoquinolines and quinolines:

In one embodiment, the castration-resistant prostate cancer in themethod of the invention is AR overexpressing castration-resistantprostate cancer, F876L mutation expressing castration-resistant prostatecancer, F876L_T877A double mutation expressing castration-resistantprostate cancer, AR-V7 expressing castration-resistant prostate cancer,d567ES expressing castration-resistant prostate cancer, and/orcastration-resistant prostate cancer characterized by intratumoralandrogen synthesis.

In one embodiment, the castration-sensitive prostate cancer in themethod of the invention is F876L mutation expressingcastration-sensitive prostate cancer, F876L_T877A double mutationcastration-sensitive prostate cancer, and/or castration-sensitiveprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, the treating of castration-sensitive prostate cancerin the method of the invention is conducted in a non-castrate setting,or as monotherapy, or when castration-sensitive prostate cancer tumor isresistant to enzalutamide, apalutamide, and/or abiraterone.

In another aspect, this invention provides a method of treating breastcancer in a subject in need thereof, wherein said subject has ARexpressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7expressing breast cancer, comprising administering to the subject atherapeutically effective amount of a selective androgen receptordegrader (SARD) compound represented by the structure of formula I:

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl; Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula I(1):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, the SARD compound is represented by is a compound offormula I(2):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, in the compounds of formulas I, I(1), and I(2), W₁,W₂, W₃, W₄, W₅, and W₆ are CH. In one embodiment, W₂ is N and W₁, W₃,W₄, W₅, and W₆ are CH. In one embodiment, W₃ is N and W₁, W₂, W₄, W₅,and W₆ are CH. In one embodiment, W₁ is N and W₂, W₃, W₄, W₅, W₆ are CH.

In one embodiment, the SARD compound is represented by represented bythe structure of formula III:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula I.

In one embodiment, in the compounds of formulas I, I(1), I(2), and III,Q is H, NO₂, COR, alkyl, alkoxy, aryl, CN, CF₃, F, Cl, Br or I. In oneembodiment, Z is CN. In one embodiment, Y is Cl or CF₃.

In one embodiment, the SARD compound is represented by the structure ofthe following compounds:

indoles:

benzimidazoles:

pyrrolo-pyridine:

indazoles:

benzotriazoles:

In another aspect, this invention provides a method of treating breastcancer in a subject in need thereof, wherein said subject has ARexpressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7expressing breast cancer, comprising administering to the subject atherapeutically effective amount of a selective androgen receptordegrader (SARD) compound represented by the structure of formula V:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl; Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula V(1):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and l are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by a compound offormula V(2):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and l are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula VI:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula IV:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, in the compound of formulas V, V(1), V(2), VI, VII,and IV, Q is H, F, Cl, Br, I, NO₂, CN, and aryl.

In one embodiment, the SARD compound is represented by the followingstructures:

indolines:

isoquinolines and quinolines:

In another aspect, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hormonal condition in a male in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound represented by the structure of formula I:

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen,CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂,C₁-C₁₂- alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl,—SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, orC₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula I(1):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, the SARD compound is represented by a compound offormula I(2):

wherein W₁, W₂, W₃, W₄, W₅, W₆, T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n areas described in the structure of formula I.

In one embodiment, in the compounds of formulas I, I(1), and I(2), W₁,W₂, W₃, W₄, W₅, and W₆ are CH. In one embodiment, W₂ is N and W₁, W₃,W₄, W₅, and W₆ are CH. In one embodiment, W₃ is N and W₁, W₂, W₄, W₅,and W₆ are CH. In one embodiment, W₁ is N and W₂, W₃, W₄, W₅, W₆ are CH.

In one embodiment, the SARD compound is represented by the structure offormula

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula I.

In one embodiment, in the compounds of formulas I, I(1), I(2), and III,Q is H, NO₂, COR, alkyl, alkoxy, aryl, CN, CF₃, F, Cl, Br or I. In oneembodiment, Z is CN. In one embodiment, Y is Cl or CF₃.

In one embodiment, the SARD compound is represented by the structure ofthe following compounds:

-   -   indoles:

benzimidazoles:

pyrrolo-pyridine:

indazoles:

benzotriazoles:

In one embodiment, the condition in the method of the invention ishypergonadism, hypersexuality, sexual dysfunction, gynecomastia,precocious puberty in a male, alterations in cognition and mood,depression, hair loss, hyperandrogenic dermatological disorders,pre-cancerous lesions of the prostate, benign prostate hyperplasia,prostate cancer and/or other androgen-dependent cancers.

In one aspect, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hormonal condition in a male in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound represented by the structure of formula V:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂- alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂- alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by a compound offormula V(1):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and l are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by a compound offormula V(2):

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, n, k, and 1 are as described inthe structure of formula V.

In one embodiment, the SARD compound is represented by represented bythe structure of formula VI:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, the SARD compound is represented by the structure offormula IV:

wherein T, Z, Y, Q, R₁, R₂, R₃, R₄, m, and n are as described in thestructure of formula V.

In one embodiment, in the compounds of formulas V, V(1), V(2), VI, VII,and IX, Q is H, F, Cl, Br, I, NO₂, CN, and aryl.

In one embodiment, the SARD compound is represented by the followingstructures:

indolines:

isoquinolines and quinolines:

In one embodiment, the condition in the method of the invention ishypergonadism, hypersexuality, sexual dysfunction, gynecomastia,precocious puberty in a male, alterations in cognition and mood,depression, hair loss, hyperandrogenic dermatological disorders,pre-cancerous lesions of the prostate, benign prostate hyperplasia,prostate cancer and/or other androgen-dependent cancers.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIGS. 1A-1C present inhibition of AR transactivation for the SARDcompounds: (FIG. 1A) 14, 18, and 20; (FIG. 1B) 11 and 12; and (FIG. 1C)11, 23 and 27; of this invention. Example 5

FIG. 2A demonstrates degradation in LNCaP cells using SARD compounds ofthis invention (11 and 20): LNCaP cells were plated in 6 well plates at1 million cells/well. The cells were maintained in serum free conditionsfor 3 days. The cells were treated as indicated in the figure,harvested, protein extracted, and Western blotted for AR. FIG. 2Bpresents the effect of AR antagonists and SARD 11 on LNCaP cell growth:LNCaP cells were plated in 96 well plates at 10,000 cells/well inRPMI+1% csFBS without phenol red. Cells were treated as indicated in thefigure in combination with 0.1 nM R1881 for 6 days with medium change onday 3. At the end of 6 days, the cells were fixed and stained withsulphorhodamine blue stain. (Example 7)

FIG. 3 presents AR-V7 degradation (PC3-AR-V7 cells) using SARD compoundsof this invention (11, 12 and 20). PC-3 prostate cancer cells were serumstably transfected with a lentivirus construct for AR-V7. Once thestable cells were selected, the cells were plated in 6 well plates at 1million cells/well. The cells were treated as indicated in the figure(μM) and Western blot performed for AR and actin. The results show thatthe SARDs have the potential to degrade truncated versions of AR suchAR-V7, while enzalutamide or ARN-509 have no effect of the AR-V7expression, suggesting that SARDs of this invention, unlike enzalutamideand ARN-509, can treat AR-V7 dependent CRPC. (Example 7)

FIG. 4 demonstrates via Western blot that 20 degraded AR-FL and AR-SV in22RV-1 cells, further supporting their use in the treatment ofAR-SV-driven CRPC. (Example 7)

FIG. 5 presents SARD degradation of AR in LNCaP cells using 11. (Example7)

FIGS. 6A-6C present SARD degradation of AR-FL and AR-V7 in 22RV-1 cellsusing (FIG. 6A) ASC-J9, (FIG. 6B) ARN-509 and (FIG. 6C) 11. (Example 7)

FIGS. 7A-7D present that 11 inhibits transactivation of AR-NTD-DBD-hinge(A/BCD) AR construct which lacks the LBD. (FIG. 7A) AR A/BCD increasesGRE-LUC reporter activity. AR A/BCD construct that lacks the ligandbinding domain or empty vector was transfected into HEK-293 cells alongwith GRE-LUC and CMV-renilla LUC. Forty eight hours after transfectioncells were harvested and luciferase assay performed. (FIG. 7B) AR A/BCDactivity was inhibited by 11. The A/BCD AR construct that lacks theligand binding domain (LBD) was transfected along with GRE-LUC andCMV-LUC. Cells were treated 24 hrs after transfection as indicated inthe figure and luciferase assay performed 48 hrs after transfection. 11(a SARD) inhibited the activity of construct lacking LBD confirming thebinding to an alternate site in addition to the LBD. (FIG. 7C) and (FIG.7D) Non-SARD antagonists ARN-509 and enzalutamide did not inhibit theactivity of this AR construct lacking the LBD, suggesting that of thecompounds tested, only SARDs of this invention have the ability toinhibit ligand independent AR activity. (Example 9)

FIGS. 8A-8B present data comparing compounds 11, 12, and 14 withgaleterone, EPI-001, and enzalutamide in AR transactivation studies.(FIG. 8A) 11, 12, and 14, galeterone, EPI-001, and enzalutamide; and(FIG. 8B) 11, galeterone, and enzaluatamide. SARDs of this inventionmore potently inhibited (AR-FL) transactivation. (Example 10)

FIGS. 9A-9D demonstrate that 11 inhibited tumor growth of an aggressiveprostate cancer (22RV-1) that expresses an AR splice variant (growthdriven by AR-V7). (FIG. 9A) 11 significantly reduced tumor volume and(FIG. 9B) tumor weight in a 22RV-1 xenograft tumor study, whereas ARantagonist enzalutamide did not have any effect compared to vehicle.(FIG. 9C) shows tumor expressed levels of AR-FL and AR-V7 were decreasedby 11 but not enzalutamide, demonstrating that in vivo activitycorrelated with AR degradation in the tumors; and (FIG. 9D) demonstratesan in vivo antiandrogenic tone in gene expression as the serum PSA inthese animals was decreased by 11 but not enzalutamide in this 22RV-1xenograft study. (Example 11)

FIGS. 10A-10C demonstrate that 11 inhibited LNCaP tumor xenograft growthvia (FIG. 10A) decreased tumor volume and (FIG. 10B) weights, and (FIG.10C) serum PSA levels in animals treated with 11 when compared tovehicle. (Example 11)

FIG. 11 presents degradation in LNCaP cells using 27, 20, 12, 23 and 32.LNCaP cells were plated in 6 well plates at 1 million cells/well. Thecells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. SARDs demonstrated selective degradation ofAR (i.e., SARD activity) in the nM range, i.e., at concentrationscomparable to their antagonist IC₅₀ values. LNCaP cells are known toexpress the AR mutant T877A, demonstrating the ability to degraderesistance conferring mutant androgen receptors. (Example 7)

FIG. 12 presents 22RV-1 Western blots: 22RV-1 cells were plated in 6well plates at 1-1.5 million cells/well in growth medium (RPMI+10% FBS).Next day, medium was changed and treated with vehicle or a dose responseof compounds 20, 24 and 30. After overnight treatment (12-16 hrs), cellswere washed in ice cold PBS and harvested by scrapping in 1 mL PBS.Cells were pelleted, protein extracted, quantified using BCA assay, andequal quantity of protein was fractionated on an SDS-PAGE. The proteinswere transferred to nylon membrane and Western blotted with AR antibody(N20 from SCBT) and actin antibody. Compounds 20, 24 and 30 were capableof degrading full length androgen receptor (AR-FL) and truncated AR(AR-SV) in 22RV-1 cells, suggesting that SARDs may be able to overcomewildtype or AR-V7 dependent prostate cancers. (Example 7)

FIG. 13 presents degradation in LNCaP cells (top) and 22RV-1 cells(bottom) using 31 vs. galeterone. Using the methods described in thelegends for FIG. 11 (LNCaP) and FIG. 12 (22RV-1), 31 was compared togaleterone (a clinical lead SARD). While 31 demonstrated SARD activityin both LNCaP (mutant AR harboring T877A mutation) and 22RV-1 (growthdependent on AR-SV lacking a LBD) cells, galeterone demonstrated littleto no AR degradation in these models. Example 7

FIG. 14 presents degradation in LNCaP cells using a dose-response of 12or ARN-509. Using the methods described in the legend for FIG. 11(LNCaP), SARD activity for 12 was compared to known SARD ARN-509. 12demonstrated activity in the nM range (100-1000 nM) whereas ARN-509 onlyhad activity at 10,000 nM. (Example 7)

FIG. 15 presents degradation in 22RV-1 cells using 31. Using the methodsdescribed in the legend for FIG. 12 (22RV-1), SARD activity for 31 wasdemonstrated as degradation of full length (AR) and truncated splicevariant (AR-V7) androgen receptor. (Example 7)

FIG. 16 presents degradation in LNCaP cells using 70 and 73. Using themethods described in the legend for FIG. 11 (LNCaP), SARD activity for70 and 73 was demonstrated at concentrations as low as 100 nM. Thisdemonstrates that benzimidazoles of this invention also demonstratepotent SARD activity. (Example 7)

FIGS. 17A-17C present biophysical data that suggests that SARDs bind tothe N-terminal domain of the AR (in addition to the LBD in theC-terminus). (FIG. 17A) A dose-dependent shift in the fluorescenceintensity, i.e., fluorescent quenching, was observed with 11 whenincubated with AR AF-1. (FIG. 17B) The fluorescence shoulder observed at307 nm, which corresponds to tyrosine residues in the AF-1, is shiftedby 11. The overall fluorescence is also markedly altered by 11. (FIG.17C) Data shown was plotted as difference in fluorescence betweencontrol and 11 treated samples (fluorescence in the absence ofcompound—fluorescence in the presence of compound), a dose dependentincrease was observed in the presence of 11. Cumulatively, these datasuggest a direct interaction between 11 and AR AF-1. (Example 12)

FIG. 18 demonstrates degradation in LNCaP cells using a SARD compound ofthis invention (100). LNCaP cells were plated in 6 well plates at 1million cells/well. The cells were maintained in serum free conditionsfor 3 days. The cells were treated as indicated in the figure,harvested, protein extracted, and Western blotted for AR. (Example 8)

FIG. 19 demonstrates via Western blot as described above for FIG. 12 ,that 100, 102, and 130 degraded AR-FL and AR-SV in 22RV-1 cells. 100,102, and 130 were capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-SV) in 22RV-1 cells, suggesting that SARDsof this invention may be able to overcome AR-V7 dependent prostatecancers. (Example 8)

FIG. 20 presents degradation in 22RV-1 cells as described above for FIG.12 , using 130 vs. galeterone. 130 was compared to galeterone (aclinical lead SARD). 130 demonstrated SARD activity in 22RV-1 (growthdependent on AR-SV, an AR variant lacking a LBD) cells which wascomparable to galeterone. (Example 8)

FIG. 21 presents degradation in LNCaP cells using 135 and 102. Using themethods described in the legend for FIG. 11 , SARD activities for 135and 102 were demonstrated. These compounds partially to fully degradedmutant AR (T877A), suggesting that SARDs of this invention such as thesemay be useful in advanced prostate cancer and/or CRPC. (Example 8)

FIG. 22 presents degradation in LNCaP cells and 22RV-1 cells using 103and 104. Using the methods described in the legends for FIG. 11 (LNCaP)and FIG. 12 (22RV-1), 103 and 104 demonstrated SARD activity in bothLNCaP (mutant AR harboring T877A mutation) and 22RV-1 (growth dependenton AR-SV lacking a LBD) cells. (Example 8)

FIG. 23 presents degradation in 22RV-1 cells using 130. Using themethods described in the legend for FIG. 12 , compound 130 demonstratedSARD activity at least at the 10 μM concentration. (Example 8)

FIG. 24 presents degradation in 22RV-1 cells using 134 and 130. Usingthe methods described in the legend for FIG. 12 , compounds 134 and 130each demonstrated SARD activity at least at the 10 μM concentration.(Example 8)

FIG. 25 presents degradation in LNCaP cells using 101, 105, 106, 107 and108. Using the methods for FIG. 11 above, 101, 105, 106, 107 and 108each demonstrated the ability to degrade the AR in the nM range.(Example 8)

FIG. 26 depicts degradation in LNCaP cells using 200 and ARN-509. LNCaPcells treated with 200 were lysed and subjected to Western blotanalysis, as described above. (Example 13 and 14)

FIG. 27 depicts degradation in 22RV-1 cells using 200 and 201. 22RV-1cells treated with 200 or 201 were lysed and subjected to Western blotanalysis, as described above. (Example 13 and 14)

FIG. 28 depicts degradation in 22RV-1 cells using 201. 22RV-1 cellstreated with 201 were lysed and subjected to Western blot analysis, asdescribed above. (Example 13 and 14)

FIGS. 29A-29O depict transactivation data, binding, and AR-FL and AR-SVdegradation for SARDs compounds of this invention. (FIG. 29A) presentstransactivation data for 42 (IC₅₀=1015 nM) and binding (K_(i)=86.1 nM).(Example 5) (FIG. 29B) presents transactivation data for 41(IC₅₀=>10,000 nM) and binding (K_(i)=84.3 nM). (Example 5) (FIG. 29C)presents (1) transactivation data for 132 (IC₅₀=978.1 nM) and binding(K_(i)=353.2 nM), (2) AR full length degradation for 132, and (3) ARsplice variant degradation for 132. (Example 6) (FIG. 29D) presentstransactivation data for 40 (IC₅₀=1032.1 nM) and binding (K_(i)=134.9nM). (Example 5) (FIG. 29E) presents (1) transactivation data for 92(IC₅₀=946.8 nM) and binding (K_(i)=nM), (2) AR full length degradationfor 92, and (3) AR splice variant D567es degradation for 92. (Example 5)(FIG. 29F) presents (1) transactivation data for 39 (IC₅₀=233.8 nM) andbinding (K_(i)=719.9 nM), (2) AR full length degradation for 39.(Example 5) (FIG. 29G) presents (1) transactivation data for 38(IC₅₀=318.4 nM) and binding (K_(i)=331.8 nM), (2) AR full lengthdegradation for 38, and (3) AR splice variant AR-V7 degradation for 38.(Example 5) (FIG. 29H) presents (1) transactivation data for 11(IC₅₀=96.4 nM) and 37 (IC₅₀=94.0 nM) and binding (K_(i)=252.6 nM), (2)AR full length degradation for 37, and (3) AR splice variant degradationfor 37. (Example 5) (FIG. 29I) presents (1) transactivation data for 36(IC₅₀=1142.0 nM) and binding (K_(i)=315.3 nM), (2) AR full lengthdegradation for 36. (Example 5) (FIG. 29J) presents (1) transactivationdata for 115 (IC₅₀=244.4 nM) and binding (K_(i)=71.5 nM), (2) AR fulllength degradation for 115, and (3) AR splice variant AR-V7 degradationfor 115. (Example 6) (FIG. 29K) presents (1) transactivation data for 35(IC₅₀=98.47 nM) and binding (K_(i)=155.7 nM) and (2) AR full lengthdegradation for 35. (Example 5) (FIG. 29L) presents (1) transactivationdata for 205 (IC₅₀=1079.1 nM) and binding (K_(i)=90.7 nM), (2) AR fulllength degradation for 205, and (3) AR splice variant AR-V7 degradationfor 205. (Example 13) (FIG. 29M) presents (1) transactivation data for114 (IC₅₀=834.7 nM) and binding (K₁=204.4 nM), (2) AR full lengthdegradation for 114, and (3) AR splice variant AR-V7 degradation for114. (Example 6) (FIG. 29N) presents transactivation data for 204(IC₅₀=1025.4 nM) and binding (K_(i)=809.6 nM). (Example 13) (FIG. 29O)presents (1) transactivation data for 34 (IC₅₀=nM) and binding(K_(i)=nM), (2) AR full length degradation for 34, and (3) AR splicevariant degradation for 34. (Example 5)

FIGS. 30A-30D present Hershberger assay: Mice (6-7 weeks old) weretreated with vehicle or indicated SARDs (100 mg/kg/day twice daily) for14 days orally. Animals were sacrificed, and seminal vesicles weightswere recorded and represented. Results: (FIG. 30A) and (FIG. 30D) SARDsdemonstrated various degrees of decreased seminal vesicles (S.V.)weight, (FIG. 30B) increased in body weight (B.Wt.), and (FIG. 30C)decreased prostate weight. This behavior is consistent with an in vivoantiandrogenic effect exerted by SARDs of this invention. (Example 16)

FIG. 31 demonstrates that 103 slowed prostate cancer tumor growth inpatient-derived xenografts (PDX) despite low levels in the plasma. SARD103 selectively accumulated in tumor. NSG mice were implanted withpatient-derived prostate cancer xenografts (PDX). Animals were treatedfor 14 days and tumor volumes were measured twice weekly, as shown inthe graph. Animals were sacrificed, 103 was extracted from the serum andtumor and measured using LC-MS/MS method. 103 selectively accumulated intumor with almost 10 times more tumor accumulation than in plasma (seeExample 16, Table 15), possibly providing an explanation for anti-tumoractivity despite low levels of SARD in the plasma. (Example 16)

FIG. 32 presents data in a mouse xenograft model treated with 103 and36. The % change in tumor volume is presented using 103 and 36. LNCaPcells were implanted (5 million cells/mouse) in NSG mice. Once tumorsreach 70-200 mm³, animals were randomized and treated with SARDs (100mg/kg/twice daily). Tumor volume was measured at regular intervals andrepresented as % change from baseline. 36 significantly inhibited tumorgrowth. (Example 16)

FIGS. 33A-33D present binding (K_(i)), transactivation (IC₅₀), half-lifein liver microsomes (MLM; t_(1/2) (minutes)) and full-length ARdegradation via Western blot of the androgen receptor with AD1 cellstreated with: (FIG. 33A) 76, (FIG. 33B) 75, (FIG. 33C) 96, and (FIG.33D) 97. Example 7

FIG. 34 presents the effect of known AR antagonists compared to SARD 96on the AR-dependent gene FKBP5. 96 suppressed the AR-responsive geneFKBP5 to a comparable extent as did enzalutamide, galeterone, andARN-509, demonstrating that 96 is a potent AR antagonist in vitro.Example 10

FIG. 35 presents the effect of known AR antagonists compared to SARD 96on the AR-dependent gene PSA. 96 suppressed the AR—responsive gene PSAto a comparable extent as did enzalutamide and greater than ARN-509. Inthis case, galeterone potently suppressed at 100 nM but the effect wasnot dose responsive, reversing at higher doses. (Example 10)

FIG. 36 presents the effect of known AR antagonists compared to SARD 96on SRB-LNCaP cell growth: LNCaP cells were plated in 96 well plates at10,000 cells/well in RPMI+1% csFBS without phenol red. Cells weretreated as indicated in the figure in combination with 0.1 nM R1881 for6 days with medium change on day 3. At the end of 6 days, the cells werefixed and stained with sulphorhodamine blue (SRB) stain. 96 demonstrateda robust and dose-dependent anti-proliferative effect whereasenzalutamide and ARN-509 only partially suppressed growth and galeteronedid not exhibit dose-dependent effects. (Example 10).

FIGS. 37A-37E depict inhibition of AR function by 11. AR ligand bindingassay was performed with GST-tagged purified human AR-LBD proteinproducing a Ki of 78.06 nM (data not shown). 11 potently inhibits ARtransactivation. AR transactivation was performed by transfecting humanAR cDNA, GRE-LUC, and CMV-renilla LUC into HEK-293 cells. Cells weretreated 24 hrs after transfection with a dose response of antagonists incombination with 0.1 nM R1881 and luciferase assay was performed 48 hrsafter transfection. Values provided are IC₅₀ (FIG. 37A). 11, but notenzalutamide, comparably inhibits transactivation of wildtype andLBD-mutant AR. Transactivation assay with 11 or enzalutamide wasperformed with wildtype AR or AR carrying commonly known LBD mutants(FIG. 37B). 11 cross-reacts with progesterone receptor (PR), butminimally with mineralocorticoid receptor (MR) or glucocorticoidreceptor (GR). Transactivation was performed by transfecting human AR,PR, GR, or MR cDNA, GRE-LUC, and CMV-renilla LUC into HEK-293 cells.Cells were treated 24 hrs after transfection with indicated doses of 11in combination with 0.1 nM progesterone (PR), dexamethasone (GR), andaldosterone (MR) and luciferase assay was performed 48 hrs aftertransfection (FIG. 37C). 11 inhibits AR-65Q transactivation.Transactivation assay with an AR cDNA that has extended poly-glutamiderepeat (65Q) was performed (FIG. 37D). 11 inhibits AR N—C interaction.Mammalian two hybrid assay was performed by transfecting HEK-293 cellswith VP16-ARNTD, Gal-4-DBD-ARLBD, Gal-4-RE-LUC, andCMV-renilla-luciferase. Cells were treated 24 hours after transfectionwith a dose response of 11 in combination with 0.1 nM R1881, andluciferase assay was performed 48 hours after transfection. Allexperiments were performed at least twice with a dose range of 1 pM to10 μM. Enza-Enzalutamide. (FIG. 37E).

FIGS. 38A-38C: 11 degrades AR and splice variant ARs. 11 degrades ARfull length in AD1 cells (left panel), AR-V567es in D567es cells (middlepanel), and AR-SV in LNCaP-95 cells (lower panel). AD1 cells expressingAR were maintained in charcoal-stripped serum containing medium, whileD567es cells expressing AR-v567es and LNCaP-95 cells expressing AR andAR-SV were maintained in growth medium for 2 days. Cells were treatedfor 24 hrs, protein extracted, and Western blot for AR and actin wasperformed (FIG. 38A). Inhibition of protein synthesis accelerates AR andAR-SV degradation by 11. 22RV1 cells (lower panel) and LNCaP cells(upper panel) were plated in growth medium and treated with 10 μM 11, 50μM cycloheximide, or combination of 11 and cycloheximide for theindicated time-points. Cells were harvested, protein extracted, andWestern blotted for AR and actin. Results from quantification of theblots are provided below (FIG. 38B). 11 promotes AR and ubiquitininteraction. LNCaP cells maintained in charcoal stripped serumcontaining medium were treated with vehicle or indicated concentrationsof 11 for 4 hrs. Protein extracts were immunoprecipitated with ARantibody and Western blot for ubiquitin was performed (FIG. 38C).

FIGS. 39A-39C: 11-dependent degradation is rapid and sustained. LNCaPcells were plated in charcoal stripped serum containing medium andtreated with 10 μM 11 in combination with 0.1 nM R1881 for the indicatedtime-points. Western blot for the AR and actin was performed (FIG. 39A).LNCaP cells maintained in RPMI+1% csFBS w/o phenol red for 2 days weretreated with 0.1 nM R1881 alone or in combination with 10 μM 11. Cellswere harvested at the indicated time-points, RNA isolated, andexpression of genes was measured and normalized to GAPDH (FIG. 39B).11-induced degradation is sustained. 22RV1 cells were plated in growthmedium containing 10% FBS and treated with 10 μM of 11 for 24 hrs.Twenty four hours after treatment, cells were washed with medium and fedwith charcoal-stripped serum containing medium. One set of cells wasimmediately harvested (time point 0 hrs), while the remaining.Subsequently, cells were harvested 24 and 72 hrs after washing the SARD.Protein was extracted and Western blot for the AR and actin wasperformed (FIG. 39C).

FIGS. 40A-40E: 11 inhibits the expression of AR-target genes andproliferation of prostate cancer cells. 11 potently inhibits theexpression of AR-target genes in LNCaP cells. LNCaP cells weremaintained in charcoal stripped serum containing medium for two days andtreated with vehicle or indicated compounds (11 or enzalutamide withdose of 1, 10, 100, 1000, and 10,000 nM) in the presence of 0.1 nM R1881for 24 hours. RNA was isolated and expression of PSA (left) or FKBP5(right) was quantified and normalized to GAPDH by realtime PCR (FIG.40A). 11 inhibits expression of a subset of genes induced by AR-V7 inPC3 cells. PC3 cells or PC3 cells stably transfected with AR-V7(PC3-ARV7) were treated with vehicle or 10 μM 11 (n=3). RNA was isolated˜16 hrs after treatment and RNA-Sequencing was performed in Ion Torrentnext-generation sequencer. Heatmap shows the top 50 genes differentiallyexpressed in PC3-AR-V7 vehicle-treated but not in 11-treated cellscompared to PC3 vehicle-treated cells. Bar graph on the right showsrepresentative genes that were differentially expressed in RNA (FIG.40B). 11 inhibits AR-target gene expression in 22RV1 cells. 22RV1 cellswere plated in charcoal stripped serum, treated with vehicle (right-mostbars of each chart) or indicated compounds (11 or enzalutamide with 10,100, 1000, and 10,000 nM) for 3 days and the expression of AR-targetgenes was measured by realtime PCR (FIG. 40C). SARDs are potentinhibitors of prostate cancer cell proliferation. LNCaP cells maintainedin charcoal stripped serum containing medium were treated with vehicleor indicated compounds (1 pM-10 μM) in the presence of 0.1 nM R1881.Cells were re-treated three days later and the cell viability wasmeasured after 6 days of treatment using SRB assay. Castration-resistantprostate cancer (CRPC) cells 22RV1, LNCaP-abl, LNCaP-95, LNCaP-EnzR, andHela cells were plated in charcoal-stripped serum containing medium andwere treated as indicated for LNCaP cells in the absence of R1881stimulation. SRB assay was performed 6 days after treatment (FIG. 40D).11 inhibits enzalutamide-resistant AR-target gene expression and growthin enzalutamide-resistant (EnzR) prostate cancer cells. EnzR LNCaP cellswere maintained in charcoal stripped serum containing medium for 2 daysand treated with vehicle, enzalutamide, or 11 (1-10,000 nM) in thepresence of 0.1 nM R1881 (FIG. 40E). Cells were harvested 24 hrs aftertreatment and expression of PSA was measured by realtime PCR. Cellproliferation in response to enzalutamide or SARDs and 0.1 nM R1881 wasperformed as described for LNCaP in panel 40D. Values in panels 40A-40Care represented as average ±S.E. with n=3.

FIGS. 41A-41B: 11 inhibits transactivation of AD1 and D567es AR and cellproliferation. 11 inhibits AD1-AR-transactivation and cell growth. ARtransactivation was performed by transfecting human GRE-LUC andCMV-renilla LUC into AD-1 cells. Cells were treated with vehicle, 0.1 nMR1881 alone or in combination with 10 μM 11 or enzalutamide 24 hrs aftertransfection and luciferase assay was performed 48 hrs aftertransfection (data not shown). AD1 cells maintained in charcoal strippedserum containing medium were treated with 10 μM UT-155 or enzalutamidein the presence of 0.1 nM R1881. Cells were re-treated three days laterand the cell viability was measured after 6 days of treatment using SRBassay. (FIG. 41A). 11 inhibits D567es-AR-transactivation and cellgrowth. AR transactivation was performed by transfecting human GRE-LUCand CMV-renilla LUC into D567es cells. Cells were treated with vehicle,10 μM 11, or enzalutamide 24 hrs after transfection and luciferase assaywas performed 48 hrs after transfection (left panel). Right: D567escells plated in growth medium were treated with vehicle, 10 μM 11 orenzalutamide (FIG. 41B). Left: Cells were re-treated three days laterand the cell viability was measured after 6 days of treatment using SRBassay (FIG. 41B).

FIGS. 42A-42D: 11 inhibits nuclear translocation and DNA binding of theAR. 11 inhibits recruitment of AR to the androgen response element(ARE). LNCaP cells were serum starved for 2 days and were treated with0.1 nM R1881 in the presence or absence of 10 μM 11 for 2 hrs.DNA-protein complex was cross-linked and AR was immunoprecipitated andits recruitment to PSA enhancer ARE was measured by realtime PCR. N=3.Values are expressed as average ±S.E. (FIG. 42A). 11 inhibits nucleartranslocation of enzalutamide-resistant AR (EnzR AR). EnzR LNCaP cellswere maintained in charcoal-stripped serum (CSS) containing medium andtreated with 10 μM 11 in the presence or absence of 0.1 nM R1881 for 4hours. Translocation of the AR into nucleus was measured byimmunofluorescence and quantified (FIG. 42B). Ligand binding of SARDswas critical for transactivation, but not for degradation. Molecularmodeling shows the critical amino acids in the AR-LBD interacting with11. The amino acids with which 11 forms hydrogen bond were mutated andtransactivation assay was performed in HEK-293 cells. Left panel: showsthat the mutants have weakened the R1881-induced transactivation. Rightpanel: was performed with a dose response of 11 in combination with 0.1nM R1881 for wildtype AR, 10 nM R1881 for Q711A, R752L, and L704A, and 1μM for N705A (FIG. 42C). Degradation of the wildtype and mutant AR by 11was evaluated by transfecting the AR constructs in HeLa cells andtreated as indicated in panel 42C for transactivation (FIG. 42D). Valuesin the graphs are IC₅₀. Enh-enhancer. ARE-Androgen Responsive Element.SRB-Sulforhodamine B. CSS—charcoal-stripped serum. DFCI—Dana-FarberCancer Institute.

FIG. 43 : The R-isomer of 11 (11R) was weaker in AR transactivation, butnot in degradation. Structures of S- and R-isomers of 11 is shown.Transactivation IC₅₀ and Western blot for the AR are shown in thefigure.

FIG. 44 : Increasing concentrations of R1881 decreased enzalutamide's,but not 11's, potential to inhibit LNCaP cell proliferation. LNCaP cellswere plated in charcoal stripped serum containing medium and treatedwith a dose response of 11 (left panel) or enzalutamide (right panel) incombination with 0.1 or 10 nM R1881. Medium was changed and the cellswere re-treated after 3 days. At the end of 6 days of treatment, cellswere fixed and SRB assay, a measure of cell viability, was performed.

FIG. 45 : 11 inhibited androgen-dependent and castration-resistant PCagrowth in vivo. LNCaP cells (5 million/mouse) mixed with matrigel wereimplanted subcutaneously on the flanks of intact NSG mice (n=6-8mice/group). Once tumors reached 100-200 mm³, animals were randomizedand treated with vehicle or 11 (50 mg/kg/day s.c.). Tumor volume wasmeasured twice weekly. Tumor weights were recorded at sacrifice. 11inhibited growth of patient-derived xenograft, Pr-3001. Pr-3001 wasimplanted as 1 mm³ fragment subcutaneously in castrated NSG mice(n=8-10/group) and the study was performed as described above. Tumorvolume was measured thrice weekly. At sacrifice tumor weights wererecorded (not shown). * significance from vehicle-treated mice atp<0.05.

FIGS. 46A-46D: 11 binds to the AR Activation Function Domain 1 (AF-1)between amino acids 244 and 360. Nuclear magnetic resonance (NMR)studies confirm the binding to AR-AF-1. 11 or enzalutamide (500 μM)dissolved in deuterated-DMSO were either added to an NMR tube alone orin combination with 5 μM GST (negative control) or GST-AF-1 purifiedprotein. The intensity of nuclear spin was measured at differentmagnetic fields (δ ppm). The peaks between 7 and 8 ppm (shown in box)correspond to the aromatic rings of 11 and enzalutamide (FIG. 46A).Waterlogsy experiment with 11 (200 μM) alone or in combination with 2 μMpurified GST-AR-AF-1 was performed as a confirmation for binding (FIG.46B). Map of various N-terminal domain fragments cloned, expressed, andcorresponding proteins purified. Purified proteins and molecular weightmarkers are shown (M.Wt. of fragments=M.Wt.+GST M.Wt. of 26 KDa) (FIG.46C). NMR studies were performed with 11 (500 μM) was performed with 5μM of various N-terminal domain fragments as described in panel 46C(FIG. 46D).

FIG. 47 : 11 binds to AR AF-1 domain based on surface plasmon resonance.Biocore assay was performed with purified activation function domain 1(AF-1) of the androgen receptor (AR) in the presence of 11.

FIG. 48 : 11 is a full antagonist with no agonist activity intransactivation studies.

FIGS. 49A and 49B: Degradation of FL AR and AR SV by selected SARDs.LNCaP (FIG. 49A) or 22RV1 (FIG. 49B) cells were plated in full-serumcontaining medium. Medium was changed to 1% charcoal-stripped serumcontaining medium and maintained in this medium for 2 days. Medium waschanged again and the cells were treated with 0.1 nM R1881 (agonist) andeither vehicle or a titration of SARD as indicated in the figure.Twenty-four hours after treatment, cells were harvested, proteinextracted, and the proteins were blotted with AR-N20 antibody. Blotswere stripped and re-probed with an actin antibody. AR—full lengthandrogen receptor; AR-SV—androgen receptor splice variant.

FIGS. 50A and 50B: SARDs antagonized transactivation of and degraded anenzalutamide resistance (Enz-R) conferring escape mutant AR. FIG. 50A:AR with phenylalanine 876 mutated to leucine (F876L), GRE-LUC, andCMV-renilla LUC were transfected in COS cells. Cells were treated 24 hafter transfection with 0.1 nM R1881 (agonist) and a dose response ofantagonists. Luciferase assay was performed 48 h after transfection.FIG. 50B: Enzalutamide-resistant LNCaP cells (MR49F) were maintained incharcoal-stripped, serum containing medium for 2 d and treated with 0.1nM R1881 (agonist) and a titration of the SARD as indicated in thefigure.

FIG. 51 : Enzalutamide-resistant LNCaP (MR49F) cellularanti-proliferation: Enzalutamide-resistant LNCaP (MR49F) cells wereplated in 1% charcoal-stripped, serum-containing medium and treated with0.1 nM R1881 and titration of antagonist as indicated in the figure.Cells were re-treated 3 d after the first treatment and the number ofviable cells measured by Cell-Titer Glo assay (Promega, Madison, Wis.).N=3. *=p<0.05.

FIGS. 52A and 52B: SARDs inhibit androgen-dependent organs in mice andrats and inhibit growth of enzalutamide-resistant prostate cancer. FIG.52A: Mice (left) or rats (right) were treated with vehicle or indicatedSARDs (40 mg/kg/day left panel) orally (n=5/group). Animals weresacrificed 14 d after treatment and weights of prostate and seminalvesicles were measured and normalized to body weight. FIG. 52B:Enzalutamide resistant LNCaP cells (5 million/mouse) were implantedsubcutaneously in male NOD SCID Gamma (NSG) mice (n=7-9 per group).Animals were castrated when the tumors reached 100-200 mm³ and allowedto regrow as castration-resistant tumors. Animals were treated orallywith vehicle (DMSO:PEG-300 15:85) or 100 mg/kg/day of SARD. Tumor volumewas measured twice weekly and represented as percent change. Values areexpressed as average ±S.E. *=p<0.05.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

Androgens act in cells by binding to the AR, a member of the steroidreceptor superfamily of transcription factors. As the growth andmaintenance of prostate cancer (PCa) is largely controlled bycirculating androgens, treatment of PCa heavily relies on therapies thattarget AR. Treatment with AR antagonists such as enzalutamide,flutamide, bicalutamide or hydroxyflutamide to disrupt receptoractivation has been successfully used in the past to reduce PCa growth.All currently available AR antagonists competitively bind AR and recruitcorepressors such as NCoR and SMRT to repress transcription of targetgenes. However, altered intracellular signaling, AR mutations, andincreased expression of coactivators lead to functional impairment ofantagonists or even transformation of antagonists into agonists. Studieshave demonstrated that mutation of W741, T877, and F876 within ARconverts bicalutamide, hydroxyflutamide, and enzalutamide respectively,to agonists. Similarly, increased intracellular cytokines recruitcoactivators instead of corepressors to AR-responsive promoterssubsequently converting bicalutamide to an agonist.

Despite initial response to androgen deprivation therapy (ADT), PCadisease progression is inevitable and the cancer emerges as castrationresistant prostate cancer (CRPC). The primary reason for castrationresistant prostate cancer (CRPC) re-emergence is re-activation ofandrogen receptor (AR) by alternate mechanisms such as:

(a) intracrine androgen synthesis;(b) expression of AR splice variants (AR-SV) that lack ligand bindingdomain (LBD);(c) AR-LBD mutations with potential to resist antagonists;(d) hyper-sensitization of AR to low androgen levels or promiscuous ARactivation via other hormones (e.g., progestins, mineralocorticoids,estrogens, glucocorticoids, etc.), possibly due to AR gene amplificationor AR mutation;(e) amplication of the AR gene within the tumor; and(f) over expression of coactivators.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which inhibit the growth ofprostate cancer (PCa) cells and tumors that are dependent on AR fulllength (AR-FL) including pathogenic and resistance-conferring mutationand/or wildtype, and/or AR splice variants (AR-SV) for proliferation.

Alternatively, a “selective androgen receptor degrader” (SARD) compoundis an androgen receptor antagonist capable of causing degradation of avariety of pathogenic mutant variant AR's and wildtype AR and hence arecapable of exerting anti-androgenism is a wide variety of pathogenicaltered cellular environments found in the disease states embodied inthis invention. In one embodiment, the SARD is orally active. In anotherembodiment, the SARD is applied topically to the site of action.

According to this invention, a “selective androgen receptor degrader”(SARD) compound is an androgen receptor antagonist that is capable ofinhibiting the growth of PCa cells and tumors that are dependent onAR-full length (AR-FL) and/or AR splice variants (AR-SV) forproliferation. In another embodiment, the SARD compound does not bind tothe ligand binding domain (LBD). In another embodiment, the SARDcompound binds to the N-terminal domain (NTD) of the AR. In anotherembodiment, the SARD compound binds to an alternate binding anddegradation domain (BDD) of the AR. In another embodiment, the SARDcompound binds both to the AR ligand binding domain (LBD) and to analternate binding and degradation domain (BDD). In another embodiment,the SARD compound binds both to the N-terminal domain (NTD) and to theligand binding domain (LBD) of the AR. In another embodiment, the SARDcompound is capable of inhibiting growth driven by the N-terminal domain(NTD)-dependent constitutively active AR-SV. In another embodiment, theSARD compound inhibits the AR through binding to a domain that isdistinct from the AR LBD. In another embodiment, the SARD compound is astrong (i.e., highly potent and highly efficacious) selective androgenreceptor antagonist, which antagonizes the AR more robustly than otherknown AR antagonists (e.g., enzalutamide, flutamide, bicalutamide andabiraterone). In another embodiment, the SARD compound is a selectiveandrogen receptor antagonist, which targets AR-SVs, which cannot beinhibited by conventional antagonists. In another embodiment, the SARDcompound exhibits AR-splice variant (AR-SV) degradation activity. Inanother embodiment, the SARD compound further exhibits AR-full length(AR-FL) degradation activity. In another embodiment, the SARD compoundexhibits AR-splice variant (AR-SV) inhibitory activity (i.e., is anAR-SV antagonist). In another embodiment, the SARD compound furtherexhibits AR-full length (AR-FL) inhibitory activity (i.e., is an AR-FLantagonist). In another embodiment, the SARD compound possesses dualAR-SV degradation and AR-SV inhibitory functions. In another embodiment,the SARD compound further possesses dual AR-FL degradation and AR-FLinhibitory functions. In another embodiment, the SARD compound is aselective androgen receptor antagonist, which targets AR-S Vs. Inanother embodiment, the SARD compound further targets AR-FLs. In anotherembodiment, the SARD compound inhibits the constitutive activation ofAR-SVs. In another embodiment, the SARD compound further inhibits theconstitutive activation of AR-FLs. In another embodiment, the SARDcompound is a selective androgen receptor antagonist, which degradesAR-full length (AR-FL) and AR splice variants (AR-SV). In anotherembodiment, the SARD compound degrades the AR through binding to adomain that is distinct from the AR LBD. In another embodiment, the SARDcompound possesses dual degradation and AR-SV inhibitory functions, thatare distinct from any available CRPC therapeutics. In anotherembodiment, the SARD compound inhibits the re-activation of the AR byalternate mechanisms such as: intracrine androgen synthesis, expressionof AR splice variants (AR-SV) that lack ligand binding domain (LBD) andAR-LBD mutations with potential to resist antagonists. In anotherembodiment, the SARD compound inhibits re-activated androgen receptorspresent in pathogenically altered cellular environments.

Nonlimiting examples of AR-splice variants (AR-SVs) are: AR-V7 andARv567es (a.k.a. AR-V12). Nonlimiting examples of AR mutationsconferring antiandrogen resistance are: W741L, T877A, H874Y, T877S, orF876L. AR-V7 is a splice variant of AR that lacks the LBD. It isconstitutively active and has been demonstrated to be responsible foraggressive PCa and resistance to endocrine therapy.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which bind to the ARthrough an alternate binding and degradation domain (BDD). In anotherembodiment, the SARD further binds the AR ligand binding domain (LBD).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) inhibitory activity (i.e., is an AR-SV antagonist). Inanother embodiment, the novel selective androgen receptor degrader(SARD) compounds, further exhibit AR-full length (AR-FL) inhibitoryactivity (i.e., is an AR-FL antagonist).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) degradation activity. In another embodiment, the novelselective androgen receptor degrader (SARD) compounds, further exhibitAR-full length (AR-FL) degradation activity.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which possess dual AR-SVdegradation and AR-SV inhibitory functions. In another embodiment, theSARDs further possess dual AR-FL degradation and AR-FL inhibitoryfunctions. In another embodiment, this invention is directed to novelselective androgen receptor degrader (SARD) compounds, which possessdual AR-SV and AR-FL degradation, and AR-SV and AR-FL inhibitoryfunctions.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, for use in treating CRPCthat cannot be treated with any other antagonist.

In one embodiment, this invention is directed to selective androgenreceptor degrader (SARD) compounds, for use in treating CRPC, bydegrading AR-S Vs.

In one embodiment, the novel SARD compounds according to this inventionmaintain their antagonistic activity in AR mutants that normally convertAR antagonists to agonists. In another embodiment, the SARD compoundsmaintain their antagonistic activity to AR mutants such as any of thefollowing mutations: W741L, T877A, H874Y, T877S, or F876L. In anotherembodiment, the SARD compounds elicit antagonistic activity within analtered cellular environment in which LBD-targeted agents are noteffective. In another embodiment, the SARD compounds elicit antagonisticactivity within an altered cellular environment in which NTD-dependentAR activity is constitutively active.

Selective Androgen Receptor Degrader (SARD) Compounds

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I, Ia, Ib, Ic, or Id:

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂O-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl,benzyl, aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ and R₄ are independently selected from hydrogen, F, Cl, Br, I, CF₃,CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionally substitutedlinear or branched alkyl, optionally substituted linear or branchedheteroalkyl, optionally substituted aryl, optionally substituted phenyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted arylalkyl, C(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, W₁, W₂, W₃, W₄, W₅, and W₆ of formula I or Ia,are each independently CH. In another embodiment, W₁ is N. In anotherembodiment, W₂ is N. In another embodiment, W₁ is CH. In anotherembodiment, W₂ is CH. In another embodiment, W₃ is N. In anotherembodiment, W₄ is N. In another embodiment, W₅ is N. In anotherembodiment, W₆ is N.

In another embodiment, W₁ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH. Inanother embodiment, W₄ is N and W₁, W₂, W₃, W₅, and W₆ are CH. Inanother embodiment, W₅ is N and W₁, W₂, W₃, W₄, and W₆ are CH. Inanother embodiment, W₆ is N and W₁, W₂, W₃, W₄, and W₅ are CH.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I(1), Ia(1), Ib(1), Ic(1), or Id(1):

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ and R₄ are independently selected from hydrogen, F, Cl, Br, I, CF₃,CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionally substitutedlinear or branched alkyl, optionally substituted linear or branchedheteroalkyl, optionally substituted aryl, optionally substituted phenyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted arylalkyl, C(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, W₁, W₂, W₃, W₄, W₅, and W₆ of formula I(1) orIa(1), are each independently CH. In another embodiment, W₁ is N. Inanother embodiment, W₂ is N. In another embodiment, W₁ is CH. In anotherembodiment, W₂ is CH. In another embodiment, W₃ is N. In anotherembodiment, W₄ is N. In another embodiment, W₅ is N. In anotherembodiment, W₆ is N.

In another embodiment, W₁ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH. Inanother embodiment, W₄ is N and W₁, W₂, W₃, W₅, and W₆ are CH. Inanother embodiment, W₅ is N and W₁, W₂, W₃, W₄, and W₆ are CH. Inanother embodiment, W₆ is N and W₁, W₂, W₃, W₄, and W₅ are CH.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I(2), Ia(2), Ib(2), Ic(2), or Id(2):

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ and R₄ are independently selected from hydrogen, F, Cl, Br, I, CF₃,CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionally substitutedlinear or branched alkyl, optionally substituted linear or branchedheteroalkyl, optionally substituted aryl, optionally substituted phenyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted arylalkyl, C(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, W₁, W₂, W₃, W₄, W₅, and W₆ of formula I or Ia,are each independently CH. In another embodiment, W₁ is N. In anotherembodiment, W₂ is N. In another embodiment, W₁ is CH. In anotherembodiment, W₂ is CH. In another embodiment, W₃ is N. In anotherembodiment, W₄ is N. In another embodiment, W₅ is N. In anotherembodiment, W₆ is N.

In another embodiment, W₁ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH. Inanother embodiment, W₄ is N and W₁, W₂, W₃, W₅, and W₆ are CH. Inanother embodiment, W₅ is N and W₁, W₂, W₃, W₄, and W₆ are CH. Inanother embodiment, W₆ is N and W₁, W₂, W₃, W₄, and W₅ are CH.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula II:

wherein

is a single or double bond;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3 or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula II(1):

wherein

-   -   is a single or double bond;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen,CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂,C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl,—SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, orC₃-C₇-cycloalkyl; Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR,alkoxy, haloalkyl, optionally substituted linear or branched alkyl,optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₃ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula III:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IV:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen,CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂,C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl,—SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, orC₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V(1):

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V(2):

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VI:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VII:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I,CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VIII:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IXa, DO, IXc, IXd, IXe, IXf, IXg or IXh:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula X:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIa, XIb, XIc, XId, XIe, XIf, XIg, or XIh:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XII:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

l is 0 or 1; and

k is 0, 1 or 2;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIIIa, XIIIb, XIIIc, XIIId, XIIIe, XIIIf, XIIIg, or XIIIh:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIV:

wherein

T is OH, OR, —NHCOCH₃, or NHCOR;

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIV(1):

wherein

T is OH, OR, —NHCOCH₃, or NHCOR;

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen,CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂,C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl,—SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, orC₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIV(2):

wherein

T is OH, OR, —NHCOCH₃, or NHCOR;

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XV:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), XVIb(2):

wherein

T is OH, OR, —NHCOCH₃, or NHCOR;

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, Q of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2) is hydrogen. In one embodiment, Q ishalogen. In one embodiment, Q is F. In one embodiment, Q is Br. In oneembodiment, Q is Cl. In one embodiment, Q is I. In one embodiment, Q isCN. In one embodiment, Q is NO₂. In one embodiment, Q is optionallysubstituted linear or branched alkyl. In one embodiment, Q is CH₃. Inone embodiment, Q is alkoxy. In one embodiment, Q is OCH₃. In oneembodiment, Q is CF₃. In one embodiment, Qis optionally substitutedphenyl. In one embodiment, Q is unsubstituted phenyl.

In one embodiment, R₃ of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2),and XVIb(2) is hydrogen. In one embodiment, R₃ is halogen. In oneembodiment, R₃ is Cl. In one embodiment, R₃ is Br. In one embodiment, R₃is I. In one embodiment, R₃ is CN. In one embodiment, R₃ is COOH. In oneembodiment, R₃ is NO₂. In one embodiment, R₃ is CF₃.

In one embodiment, R₄ of compound of formulas I, I(1)-I(2), Ia-Id,Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2),and XV is hydrogen. In one embodiment, R₄ of compound of formulas I,I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1), V(1)-V(2),XIV, XIV(1)-XIV(2), and XV is halogen. In one embodiment, R₄ of compoundof formulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II-VII,II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), and XV is F. In one embodiment, R₄of compound of formulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2),II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), and XV is Cl. In oneembodiment, R₄ of compound of formulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1),Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), and XV is Br.In one embodiment, R₄ of compound of formulas I, I(1)-I(2), Ia-Id,Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2),and XV is I. In one embodiment, R₄ of compound of formulas I, I(1)-I(2),Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV,XIV(1)-XIV(2), and XV is CN. In one embodiment, R₄ of compound offormulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1),V(1)-V(2), XIV, XIV(1)-XIV(2), and XV is COOH. In one embodiment, R₄ ofcompound of formulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2),II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), and XV is NO₂. In oneembodiment, R₄ of compound of formulas I, I(1)-I(2), Ia-Id, Ia(1)-Id(1),Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), and XV isCF₃. In one embodiment, R₄ of compound of formulas I, I(1)-I(2), Ia-Id,Ia(1)-Id(1), Ia(2)-Id(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2),and XV is methyl. In one embodiment, R₄ of compound of formulas I,I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II(1), V(1)-V(2), XIV,XIV(1)-XIV(2), and XV is COOR.

In one embodiment, Z of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1), XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2) is CN. In another embodiment, Z is NO₂. Inanother embodiment, Z is COOH. In another embodiment, Z is COR. Inanother embodiment, Z is NHCOR. In another embodiment, Z is CONHR. Inanother embodiment, Z is in the para position.

In one embodiment, Y of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1), XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) and XVIb(2) is CF₃. In another embodiment, Y is F. In anotherembodiment, Y is I. In another embodiment, Y is Br. In anotherembodiment, Y is Cl. In another embodiment, Y is CN. In anotherembodiment, Y is C(R)₃. In another embodiment, Y is in the metaposition.

In one embodiment, Z of compound of formulas I, I(1)-I(2), Ia-Id,Ia(1)-Id(1), Ia(2)-Id(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1), XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), XVIb(2) is CN and Y is CF₃. In another embodiment, Zis NO₂ and Y is CF₃. In another embodiment, Z is NO₂ and Y is halogen.In another embodiment, Z is CN and Y is halogen. In another embodiment,Z of compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-e2),II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1),XIV(2), XV,XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) and XVIb(2) is in thepara position and Y is in the meta position.

In one embodiment, R₂ of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II(1), V(1)-V(2), XIV, XIV(1)-XIV(2), XV,XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) and XVIb(2) is hydrogen. In oneembodiment, R₂ is halogen. In one embodiment, R₂ is CN. In oneembodiment, R₂ is NO₂. In one embodiment, R₂ is C₁-C₁₂-alkyl. In oneembodiment, R₂ is aryl. In one embodiment, R₂ is phenyl. In oneembodiment, R₂ is COOH. In one embodiment, R₂ is COOR. In oneembodiment, R₂ is COR. In one embodiment, R₂ is NHCOR. In oneembodiment, R₂ is CONHR. In one embodiment, R₂ is OH. In one embodiment,R₂ is OR. In one embodiment, R₂ is SH. In one embodiment, R₂ is SR. Inone embodiment, R₂ is NH₂. In one embodiment, R₂ is NHR. In oneembodiment, R₂ is N(R)₂. In one embodiment, R₂ is C₁-C₁₂-haloalkyl. Inone embodiment, R₂ is O—C₁-C₁₂-alkyl. In one embodiment, R₂ isO—C₁-C₁₂-haloalkyl. In one embodiment, R₂ is —SO₂-aryl. In oneembodiment, R₂ is —SO₂-phenyl. In one embodiment, R₂ is —CO-aryl. In oneembodiment, R₂ is arylalkyl. In one embodiment, R₂ is benzyl. In oneembodiment, R₂ is C₃-C₇-cycloalkyl.

In one embodiment, R₁ of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VII, II(1), V(1)-V(2), XIV andXIV(1)-XIV(2), XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2) isCH₃. In another embodiment, R₁ is CF₃.

In one embodiment, T of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2),XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), XVIb(2) is OH. In anotherembodiment, T is OCH₃. In another embodiment, T is

In one embodiment, R of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1), XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2) is alkyl. In another embodiment, R ishaloalkyl. In another embodiment, R is dihaloalkyl. In anotherembodiment, R is trihaloalkyl. In another embodiment, R is CH₂F. Inanother embodiment, R is CHF₂. In another embodiment, R is CF₃. Inanother embodiment, R is CF₂CF₃. In another embodiment, R is aryl. Inanother embodiment, R is phenyl. In another embodiment, R is F. Inanother embodiment, R is Cl. In another embodiment, R is Br. In anotherembodiment, R is I. In another embodiment, R is alkenyl. In anotherembodiment, R is hydroxyl (OH).

In one embodiment, m of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2),and XVIb(2) is 1. In one embodiment, m is 2. In one embodiment, m is 3.

In one embodiment, n of compound of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VII, II(1), V(1)-V(2), XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2) is 1. In oneembodiment, n is 2. In one embodiment, m is 3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound selected from the followingstructures:

Indoles:

Benzimidazoles:

Pyrrolo-pyridine:

Indazoles:

Benzotriazoles:

Indolines:

Isoquinolines and Quinolines:

Carbazoles:

The term “heterocycloalkyl” group refers, in one embodiment, to acycloalkyl structure comprising in addition to carbon atoms, sulfur,oxygen, nitrogen or any combination thereof, as part of the ring. Inanother embodiment, the heterocycloalkyl is a 3-12 membered ring. Inanother embodiment, the heterocycloalkyl is a 6 membered ring. Inanother embodiment, the heterocycloalkyl is a 5-7 membered ring. Inanother embodiment, the heterocycloalkyl is a 4-8 membered ring. Inanother embodiment, the heterocycloalkyl group may be unsubstituted orsubstituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido,alkylamido, dialkylamido, cyano, nitro, CO₂H, amino, alkylamino,dialkylamino, carboxyl, thio and/or thioalkyl. In another embodiment,the heterocycloalkyl ring may be fused to another saturated orunsaturated cycloalkyl or heterocyclic 3-8 membered ring. In anotherembodiment, the heterocyclic ring is a saturated ring. In anotherembodiment, the heterocyclic ring is an unsaturated ring. In anotherembodiment, the heterocycloalkyl is piperidine, tetrahydrofuran,morpholine, pyrrolidine, or piperazine.

The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclicring comprising carbon and hydrogen atoms. A cycloalkyl group can haveone or more carbon-carbon double bonds in the ring so long as the ringis not rendered aromatic by their presence. Examples of cycloalkylgroups include, but are not limited to, (C₃-C₇) cycloalkyl groups, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl,and saturated cyclic and bicyclic terpenes and (C₃-C₇) cycloalkenylgroups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclicterpenes. A cycloalkyl group can be unsubstituted or substituted by oneor two substituents. Preferably, the cycloalkyl group is a monocyclicring or bicyclic ring.

The term “alkyl” refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1˜4 carbons. In another embodiment, the cyclic alkyl group has 3-8carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons.In another embodiment, the branched alkyl is an alkyl substituted byalkyl side chains of 1 to 5 carbons. In another embodiment, the branchedalkyl is an alkyl substituted by haloalkyl side chains of 1 to 5carbons. The alkyl group may be unsubstituted or substituted by ahalogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thioand/or thioalkyl.

The term “heteroalkyl” refers to any alkyl as defined above wherein oneor more of the carbons are being replaced by oxygen, nitrogen, sulfur,phosphorous or combination thereof.

An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyland aryl are as defined above. An example of an arylalkyl group is abenzyl group.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bonds. The alkenyl group may have one doublebond, two double bonds, three double bonds, etc. In another embodiment,the alkenyl group has 2-12 carbons. In another embodiment, the alkenylgroup has 2-6 carbons. In another embodiment, the alkenyl group has 2-4carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl,cyclohexenyl, etc. The alkenyl group may be unsubstituted or substitutedby a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido,nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system. In another embodiment, the aryl isphenyl.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. It isunderstood by a person skilled in the art that when T, Q, R₂ R₃ or R₄ inthe compounds of the present invention is OR, then the corresponding Ris not OH.

In one embodiment, the term “halogen” or “halo” refers to a halogen,such as F, Cl, Br or I.

In one embodiment, this invention provides for the use of a compound asherein described and/or, its derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or combinations thereof.

In one embodiment, the methods of this invention make use of“pharmaceutically acceptable salts” of the compounds, which may beproduced, by reaction of a compound of this invention with an acid orbase.

Suitable pharmaceutically acceptable salts of amines of the compounds ofthe methods of this invention may be prepared from an inorganic acid orfrom an organic acid. In one embodiment, examples of inorganic salts ofamines are bisulfates, borates, bromides, chlorides, hemisulfates,hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates,persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonicacids (alkylsulfonates, arylsulfonates, halogen substitutedalkylsulfonates, halogen substituted arylsulfonates), sulfonates andthiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,algenates, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxylates, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonates,gluconates, glutamates, glycolates, glucorates, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamates, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates,hydrofluorates, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, nitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, pectinates, phenylpropionates, palmitates, pantothenates,polygalacturates, pyruvates, quinates, salicylates, succinates,stearates, sulfanilates, subacetates, tartarates, theophyllineacetates,p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates,undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earth metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procaine,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the methods of this invention make use of apharmaceutically acceptable salt of the compounds of this invention. Inone embodiment, the methods of this invention make use of apharmaceutically acceptable salt of compounds of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2). In one embodiment, the methods of thisinvention make use of a salt of an amine of the compounds of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2) of this invention. In oneembodiment, the methods of this invention make use of a salt of a phenolof the compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2), and XVIb(2) of this invention.

In one embodiment, the methods of this invention make use of a freebase, free acid, non charged or non-complexed compounds of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2) and/or its isomer,pharmaceutical product, hydrate, polymorph, or combinations thereof.

In one embodiment, the methods of this invention make use of an isomerof a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2).In one embodiment, the methods of this invention make use of apharmaceutical product of a compound of formulas I I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2). In one embodiment, the methods of thisinvention make use of a hydrate of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2). In one embodiment, the methods of thisinvention make use of a polymorph of a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2). In one embodiment, themethods of this invention make use of a metabolite of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), and XVIb(2). In anotherembodiment, the methods of this invention make use of a compositioncomprising a compound of formulas I I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2), and XVIb(2), as described herein, or, in another embodiment, acombination of isomer, metabolite, pharmaceutical product, hydrate,polymorph of a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2), and XVIb(2).

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the term “isomer” is meant to encompass opticalisomers of the SARD compound. It will be appreciated by those skilled inthe art that the SARDs of the present invention contain at least onechiral center. Accordingly, the SARDs used in the methods of the presentinvention may exist in, and be isolated in, optically-active or racemicforms. Some compounds may also exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARDs are the pure (R)-isomers. In another embodiment, the SARDs are thepure (S)-isomers. In another embodiment, the SARDs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARDs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

In another embodiment, this invention further includes hydrates of thecompounds. The invention also includes use of N-oxides of the aminosubstituents of the compounds described herein.

In one embodiment, the term “hydrate” refers to hemihydrate,monohydrate, dihydrate, trihydrate or others, as known in the art.

This invention provides, in other embodiments, use of metabolites of thecompounds as herein described. In one embodiment, “metabolite” means anysubstance produced from another substance by metabolism or a metabolicprocess.

In one embodiment, the compounds of this invention are preparedaccording to Examples 1-4.

Biological Activity of Selective Androgen Receptor Degraders

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), and XVIb(2) as described above. In another embodiment,the prostate cancer is advanced prostate cancer, castration resistantprostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC(nmCRPC), high-risk nmCRPC or any combination thereof. In anotherembodiment, the prostate cancer depends on AR-FL and/or AR-SV forproliferation. In another embodiment, the subject further receivesandrogen deprivation therapy (ADT). In another embodiment, the subjecthas failed androgen deprivation therapy (ADT). In another embodiment,the cancer is resistant to treatment with an androgen receptorantagonist. In another embodiment, the cancer is resistant to treatmentwith enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509,ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide,hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole,spironolactone, or any combination thereof.

In another embodiment, administering the compound to a subject reducesthe levels of AR, AR-full length (AR-FL), AR-FL with antiandrogenresistance-conferring AR-LBD mutations, AR-splice variant (AR-SV),gene-amplified AR, or any combination thereof, in said subject. In oneembodiment, this invention provides a method of treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of prostate cancer (PCa) and its symptoms, or increasing thesurvival of a male subject suffering from prostate cancer comprisingadministering to said subject a therapeutically effective amount of acompound or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof, said compoundselected from the following structures:

Indoles:

Benzimidazoles:

Pyrrolo-pyridine:

Indazoles:

Benzotriazoles:

Indolines:

Isoquinolines and Quinolines:

Carbazoles:

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, flutamide, bicalutamide,abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9,flutamide, hydroxyflutamide, nilutamide, cyproterone acetate,ketoconazole, spironolactone, or any combination thereof. In anotherembodiment, administering the compound to a subject reduces the levelsof AR, AR-full length (AR-FL), AR-FL with antiandrogenresistance-conferring AR-LBD mutations, AR-splice variant (AR-SV),gene-amplified AR, or any combination thereof, in said subject.

In one embodiment, the methods of this invention are directed totreating, suppressing, reducing the incidence, reducing the severity,inhibiting, providing palliative care, or increasing the survival of asubject suffering from prostate cancer. In one embodiment, the methodsof this invention are directed to methods of treating, suppressing,reducing the incidence, reducing the severity, inhibiting, providingpalliative care, or increasing the survival of advanced prostate cancerin a subject.

In one embodiment, the methods of this invention are directed totreating, suppressing, reducing the incidence, reducing the severity,inhibiting, providing palliative care, or increasing the survival of asubject suffering from castration resistant prostate cancer (CRPC). Inone embodiment, the methods of this invention are directed to treating,suppressing, reducing the incidence, reducing the severity, inhibiting,providing palliative care, or increasing the survival of a subjectsuffering from metastatic castration resistant prostate cancer (mCRPC).In one embodiment, the methods of this invention are directed totreating, suppressing, reducing the incidence, reducing the severity,inhibiting, providing palliative care, or increasing the survival of asubject suffering from non-metastatic castration resistant prostatecancer (nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. Inanother embodiment, the subject has high or increasing prostate specificantigen (PSA) levels.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a SARD compound or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof, said compound is represented by a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) and XVIb(2) or any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205 and300-308.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of advanced prostate cancer and its symptoms,or increasing the survival of a male subject suffering from advancedprostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) and XVIb(2) orany one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205 and 300-308.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of metastatic prostate cancer and itssymptoms, or increasing the survival of a male subject suffering frommetastatic prostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) and XVIb(2) orany one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205 and 300-308

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of a male subjectsuffering from castration resistant prostate cancer (CRPC) comprisingadministering to said subject a therapeutically effective amount of aSARD compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,said compound is represented by a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) and XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205 and 300-308.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used for treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of castration resistant prostate cancer (CRPC) and itssymptoms, or increasing the survival of men with castration resistantprostate cancer. In another embodiment, the CRPC is metastatic CRPC(mCRPC). In another embodiment, the CRPC is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. In anotherembodiment, the subject further receives androgen deprivation therapy.

As used herein, the terms “increase” and “prolong” may be usedinterchangeably having all the same meanings and qualities, whereinthese terms may in one embodiment refer to a lengthening of time. Inanother embodiment, as used herein, the terms “increase”, “increasing”“increased” may be used interchangeably and refer to an entity becomingprogressively greater (as in size, amount, number, or intensity),wherein for example the entity is sex hormone-binding globulin (SHBG) orprostate-specific antigen (PSA).

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing metastasis-free survival(MFS) in a subject suffering from non-metastatic prostate cancer. In oneembodiment, the non-metastatic prostate cancer is non-metastaticadvanced prostate cancer. In another embodiment, the non-metastaticprostate cancer is non-metastatic CRPC (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used to provide a dual action,for example treating prostate cancer and preventing metastases. In oneembodiment, the prostate cancer being treated is advanced prostatecancer. In one embodiment, the prostate cancer being treated iscastration resistant prostate cancer (CRPC). In one embodiment, theprostate cancer being treated is metastatic CRPC (mCRPC). In oneembodiment, the prostate cancer being treated is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC.

Men with advanced prostate cancer who are at high risk for progressionto castration resistant prostate cancer (CRPC), in one embodiment, aremen on ADT with serum total testosterone concentrations greater than 20ng/dL or in another embodiment, men with advanced prostate cancer who atthe time of starting ADT had either (1) confirmed Gleason pattern 4 or 5prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time<3 months, (4) a PSA≥20 ng/mL, or (5) a PSA relapse in <3 years afterdefinitive local therapy (radical prostatectomy or radiation therapy).

Men with high risk non-metastatic castration resistant prostate cancer(high-risk nmCRPC) may include those with rapid PSA doubling times,having an expected progression-free survival of approximately 18 monthsor less (Miller K, Moul J W, Gleave M, et al. 2013. Phase III,randomized, placebo-controlled study of once-daily oral zibotentan(ZD4054) in patients with non-metastatic castration-resistant prostatecancer. Prostate Canc Prost Dis. February; 16:187-192). This relativelyrapid progression of their disease underscores the importance of noveltherapies for these individuals. In one embodiment, the PSA levels aregreater than 8 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the PSA doubling time is less than 8 months in a subjectsuffering from high-risk nmCRPC. In another embodiment, the PSA doublingtime is less than 10 months in a subject suffering from high-risknmCRPC. In one embodiment, the total serum testosterone levels aregreater than 20 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the serum free testosterone levels are greater thanthose observed in an orchidectomized male in a subject suffering fromhigh-risk nmCRPC.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with LHRH agonist orantagonist for increasing the progression free survival or overallsurvival of a subject suffering from prostate cancer. In anotherembodiment, the prostate cancer is advanced prostate cancer. In anotherembodiment, the prostate cancer is castration resistant prostate cancer(CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). Inanother embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, thesubject is surgically castrated. In another embodiment, the subject ischemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-programmeddeath receptor 1 (anti-PD-1) drugs (e.g., AMP-224, nivolumab,pembrolizumab, pidilizumab, AMP-554, and the like) for increasing theprogression free survival or overall survival of a subject sufferingfrom prostate cancer. In another embodiment, the prostate cancer isadvanced prostate cancer. In another embodiment, the prostate cancer iscastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject is surgically castrated. Inanother embodiment, the subject is chemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-PD-L1 drugs oranti-CTLA-4 drugs (anti-PD-L1 drugs include, but are not limited to,BMS-936559, atezolizumab, durvalumab, avelumab, and MPDL3280A.Anti-CTLA-4 drugs include, but are not limited to, ipilimumab andtremelimumab) for increasing the progression free survival or overallsurvival of a subject suffering from prostate cancer. In anotherembodiment, the prostate cancer is advanced prostate cancer. In anotherembodiment, the prostate cancer is castration resistant prostate cancer(CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). Inanother embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, thesubject is surgically castrated. In another embodiment, the subject ischemically castrated.

In certain embodiments, treatment of prostate cancer, advanced prostatecancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningfulimprovement in prostate cancer related symptoms, function and/orsurvival. Clinically meaningful improvements include but are not limitedto increasing radiographic progression free survival (rPFS) if cancer ismetastatic, and increasing metastasis-free survival (MFS) if cancer isnon-metastatic.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing the survival of men withcastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject further receives androgendeprivation therapy.

In one embodiment, levels of prostate specific antigen (PSA) considerednormal are age dependent. In one embodiment, levels of prostate specificantigen (PSA) considered normal are dependent on the size of a malesubject's prostate. In one embodiment, PSA levels in the range between2.5-10 ng/mL are considered “borderline high”. In another embodiment,PSA levels above 10 ng/mL are considered “high”.

In one embodiment, the rate of change or “PSA velocity” is high. In oneembodiment, a rate of change or “PSA velocity” greater than 0.75/year isconsidered high.

In one embodiment, this invention provides a method of lowering serumprostate specific antigen (PSA) levels in a male subject suffering fromprostate cancer, advanced prostate cancer, metastatic prostate cancer orcastration resistant prostate cancer (CRPC), comprising administering atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by thestructure of formula I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orany one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308. In one embodiment, this invention isdirected to treatment of a subject with high or increasing PSA levelscomprising administering a SARD compound of this invention. In oneembodiment, this invention is directed to treatment of a subject withhigh or increasing PSA levels despite ongoing ADT or a history of ADT,surgical castration or despite treatment with antiandrogens and/or LHRHagonist. In another embodiment, the treatment makes use of compounds offormula I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or any one ofcompounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, 300-308.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II, II(1), III, IXa, IXe-IXj, XIa,XIe-XIj, XIIIa, or XIIIe-XIIIj or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is compound 11.In another embodiment, the compound is compound 11R. In anotherembodiment, the compound is compound 12. In another embodiment, thecompound is compound 13. In another embodiment, the compound is compound14. In another embodiment, the compound is compound 15. In anotherembodiment, the compound is compound 16. In another embodiment, thecompound is compound 17. In another embodiment, the compound is compound18. In another embodiment, the compound is compound 19. In anotherembodiment, the compound is compound 20. In another embodiment, thecompound is compound 21. In another embodiment, the compound is compound22. In another embodiment, the compound is compound 23. In anotherembodiment, the compound is compound 24. In another embodiment, thecompound is compound 25. In another embodiment, the compound is compound26. In another embodiment, the compound is compound 27. In anotherembodiment, the compound is compound 30. In another embodiment, thecompound is compound 31. In another embodiment, the compound is compound32. In another embodiment, the compound is compound 33. In anotherembodiment, the compound is compound 34. In another embodiment, thecompound is compound 35. In another embodiment, the compound is compound36. In another embodiment, the compound is compound 37. In anotherembodiment, the compound is compound 38. In another embodiment, thecompound is compound 39. In another embodiment, the compound is compound40. In another embodiment, the compound is compound 41. In anotherembodiment, the compound is compound 42. In another embodiment, thecompound is compound 43. In another embodiment, the compound is compound44. In another embodiment, the compound is compound 45. In anotherembodiment, the compound is compound 46. In another embodiment, thecompound is compound 70. In another embodiment, the compound is compound71. In another embodiment, the compound is compound 72. In anotherembodiment, the compound is compound 73. In another embodiment, thecompound is compound 74. In another embodiment, the compound is compound75. In another embodiment, the compound is compound 76. In anotherembodiment, the compound is compound 77. In another embodiment, thecompound is compound 78. In another embodiment, the compound is compound79. In another embodiment, the compound is compound 80. In anotherembodiment, the compound is compound 90. In another embodiment, thecompound is compound 91. In another embodiment, the compound is compound92. In another embodiment, the compound is compound 93. In anotherembodiment, the compound is compound 94. In another embodiment, thecompound is compound 95. In another embodiment, the compound is compound96. In another embodiment, the compound is compound 97. In anotherembodiment, the compound is compound 98. In another embodiment, thecompound is compound 300. In another embodiment, the compound iscompound 301. In another embodiment, the compound is compound 302. Inanother embodiment, the compound is compound 303. In another embodiment,the compound is compound 304. In another embodiment, the compound iscompound 211. In another embodiment, the compound is compound 305. Inanother embodiment, the compound is compound 306. In another embodiment,the compound is compound 307. In another embodiment, the compound iscompound 308.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas II, II(1),IV-VIII, V(1)-V(2), IXb-IXd, X, XIb-XId, XII, or XIIIb-XIIId or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is compound 100. In another embodiment, the compound iscompound 101. In another embodiment, the compound is compound 102. Inanother embodiment, the compound is compound 103. In another embodiment,the compound is compound 104. In another embodiment, the compound iscompound 105. In another embodiment, the compound is compound 106. Inanother embodiment, the compound is compound 107. In another embodiment,the compound is compound 108. In another embodiment, the compound iscompound 109. In another embodiment, the compound is compound 110. Inanother embodiment, the compound is compound 111. In another embodiment,the compound is compound 112. In another embodiment, the compound iscompound 113. In another embodiment, the compound is compound 114. Inanother embodiment, the compound is compound 115. In another embodiment,the compound is compound 130. In another embodiment, the compound iscompound 131. In another embodiment, the compound is compound 132. Inanother embodiment, the compound is compound 133. In another embodiment,the compound is compound 134. In another embodiment, the compound iscompound 135. In another embodiment, the compound is compound 136. Inanother embodiment, the compound is compound 137.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas XIV,XIV(1)-XIV(2), or XV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is compound 200. In anotherembodiment, the compound is compound 201. In another embodiment, thecompound is compound 202. In another embodiment, the compound iscompound 203. In another embodiment, the compound is compound 204. Inanother embodiment, the compound is compound 205.

In one embodiment, this invention provides a method of secondaryhormonal therapy that reduces serum PSA in a male subject suffering fromcastration resistant prostate cancer (CRPC) comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the castration is surgical castration.

In another embodiment, with regards to the methods described above, theprostate cancer depends on AR-FL and/or AR-SV for proliferation. Inanother embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the prostate canceror other cancer is resistant to treatment with enzalutamide, flutamide,bicalutamide, abiraterone, ARN-509, apalutamide, darolutamide, ODM-201,EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administration of thecompounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2)reduces the levels of AR, AR-full length (AR-FL), AR-FL withantiandrogen resistance-conferring AR-LBD mutations, AR-splice variant(AR-SV), gene-amplified AR, poly-Q AR, or any combination thereof, inthe subject. In another embodiment, the castration is surgicalcastration. In another embodiment, the castration is chemicalcastration. In another embodiment, the CRPC is metastatic CRPC (mCRPC).In another embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, themethod further increases radiographic progression free survival (rPFS)in a subject suffering from a metastatic cancer. In another embodiment,the method further increases metastasis-free survival (MFS) in a subjectsuffering from non-metastatic cancer. In one embodiment, the method maybe used to provide a dual action, for example treating prostate cancerand preventing metastases. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject further receives LHRH agonist or antagonist. Inanother embodiment, the LHRH agonist is leuprolide acetate. In anotherembodiment, the subject had undergone orchidectomy. In anotherembodiment, the subject has high or increasing prostate specific antigen(PSA) levels. In another embodiment, the subject is a prostate cancerpatient. In another embodiment, the subject is a prostate cancer patienton ADT. In another embodiment, the subject is a prostate cancer patienton ADT with castrate levels of total T. In another embodiment, thesubject is an advanced prostate cancer patient. In another embodiment,the subject is an advanced prostate cancer patient on ADT. In anotherembodiment, the subject is an advanced prostate cancer patient on ADTwith castrate levels of total T. In another embodiment, the subject is aCRPC patient. In another embodiment, the subject is a CRPC patient onADT. In another embodiment, the subject is a CRPC patient on ADT withcastrate levels of total T. In another embodiment, the subject is ametastatic castration resistant prostate cancer (mCRPC) patient. Inanother embodiment, the subject is a mCRPC patient maintained on ADT. Inanother embodiment, the subject is a mCRPC patient maintained on ADTwith castrate levels of total T. In another embodiment, the subject is anon-metastatic castration resistant prostate cancer (nmCRPC) patient. Inanother embodiment, the subject is an nmCRPC patient maintained on ADT.In another embodiment, the subject is an nmCRPC patient maintained onADT with castrate levels of total T. In one embodiment, the nmCRPC ishigh-risk nmCRPC. In another embodiment, the method further treats,suppresses, reduces the incidence, reduces the severity, or inhibitsadvanced prostate cancer. In another embodiment, the method furtherprovides palliative treatment of advanced prostate cancer.

In one embodiment, this invention is directed to a method of reducingthe levels of AR, AR-full length, AR-FL with antiandrogenresistance-conferring AR-LBD mutations, polyQ AR, and/or AR-splicevariants in a subject, comprising administering to said subject atherapeutically effective amount of a SARD compound according to thisinvention, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the reduction is achieved by degradation of saidAR, AR-full length (AR-FL), polyQ AR, and/or AR-splice variants (AR-SV).In another embodiment, the reduction is achieved by inhibition of saidAR, AR-full length (AR-FL) and/or AR-splice variants (AR-SV). In anotherembodiment, the reduction is achieved by dual AR-SV/AR-FL degradationand AR-SV/AR-FL inhibitory functions.

In one embodiment, this invention is directed to a method of reducingthe levels of AR-splice variants in a subject, comprising administeringto said subject a therapeutically effective amount of a SARD compoundaccording to this invention, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the method further reduces the levels ofAR-full length (AR-FL) in the subject. In another embodiment, thereduction is achieved by degradation of said AR-splice variants (AR-SV).In another embodiment, the reduction is further achieved by degradationof said AR-FL. In another embodiment, the reduction is achieved byinhibition of said AR-splice variants (AR-SV). In another embodiment,the reduction is further achieved by inhibition of said AR-FL. Inanother embodiment, the reduction is achieved by dual AR-SV degradationand AR-SV inhibitory functions. In another embodiment, the reduction isachieved by dual AR-FL degradation and AR-FL inhibitory functions.

In one embodiment, “a subject suffering from castration resistantprostate cancer” refers to a subject which has been previously treatedwith androgen deprivation therapy (ADT), has responded to the ADT andcurrently has a serum PSA>2 ng/mL or >2 ng/mL and representing a 25%increase above the nadir achieved on the ADT. In another embodiment, theterm refers to a subject which despite being maintained on androgendeprivation therapy is diagnosed to have serum PSA progression. Inanother embodiment, the subject has a castrate level of serum totaltestosterone (<50 ng/dL). In another embodiment, the subject has acastrate level of serum total testosterone (<20 ng/dL). In anotherembodiment, the subject has rising serum PSA on two successiveassessments at least 2 weeks apart. In another embodiment, the subjecthad been effectively treated with ADT. In another embodiment, thesubject has a history of serum PSA response after initiation of ADT. Inanother embodiment, the subject has been treated with ADT and had aninitial serum PSA response, but now has a serum PSA>2 ng/mL and a 25%increase above the nadir observed on ADT. In one embodiment, the CRPC ismetastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC.

The term “serum PSA response” refers to, in one embodiment, at least 90%reduction in serum PSA value prior to the initiation of ADT, to <10ng/mL or undetectable level of serum PSA (<0.2 ng/mL) at any time, or inanother embodiment to at least 50% decline from baseline in serum PSA,or in another embodiment to at least 90% decline from baseline in serumPSA, or in another embodiment to at least 30% decline from baseline inserum PSA, or in another embodiment to at least 10% decline frombaseline in serum PSA.

The term “serum PSA progression” refers to in one embodiment, a 25% orgreater increase in serum PSA and an absolute increase of 2 ng/ml ormore from the nadir; or in another embodiment, to serum PSA>2 ng/mL,or >2 ng/mL and a 25% increase above the nadir after the initiation ofandrogen deprivation therapy (ADT).

In another embodiment, the term “nadir” refers to the lowest PSA levelwhile a patient is undergoing ADT.

Testosterone can be measured as “free” (that is, bioavailable andunbound) or as “total” (including the percentage which is protein boundand unavailable) serum levels. In one embodiment, total serumtestosterone comprises free testosterone and bound testosterone.

The methods of this invention comprise administering a combination offorms of ADT and a compound of this invention. In one embodiment, formsof ADT include a LHRH agonist. In another embodiment, the LHRH agonistincludes leuprolide acetate (Lupron®)(U.S. Pat. Nos. 5,480,656;5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 whichare all incorporated by reference herein) or goserelin acetate(Zoladex®) (U.S. Pat. Nos. 7,118,552; 7,220,247; 7,500,964 which are allincorporated by reference herein). In one embodiment, forms of ADTinclude an LHRH antagonist. In another embodiment, the LHRH antagonistincludes degarelix. In another embodiment, the LHRH antagonist includesabarelix. In one embodiment, forms of ADT include reversibleantiandrogens. In another embodiment, the antiandrogens includebicalutamide, flutamide, finasteride, dutasteride, enzalutamide,nilutamide, chlormadinone, abiraterone or any combination thereof. Inone embodiment, forms of ADT include bilateral orchidectomy.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a combination of one or more formsof ADT and a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the subject has failed androgen deprivationtherapy (ADT).

In one embodiment, this invention provides a method of lowering serumPSA levels in a male subject suffering from castration resistantprostate cancer (CRPC) comprising administering a therapeuticallyeffective amount of a combination of one or more forms of ADT and acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the subject has failed androgen deprivation therapy (ADT).

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of an antiandrogen and a compound ofthis invention. In one embodiment, the methods of this inventioncomprise administering a therapeutically effective amount of an LHRHagonist and a compound of this invention. In one embodiment, the methodsof this invention comprise administering a therapeutically effectiveamount of an antiandrogen, LHRH agonist and a compound of thisinvention. In another embodiment, the compound is a compound of formulasI, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or any one ofcompounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, or 300-308.

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of a lyase inhibitor (e.g.,abiraterone) and a compound of this invention. In another embodiment,the compound is a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) or any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, or 300-308.

In another embodiment, this invention provides a method for androgendeprivation therapy (ADT) in a subject, comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, said subject has prostate cancer. Inanother embodiment, the prostate cancer is castration resistant prostatecancer (CRPC). In another embodiment, the CRPC is metastatic CRPC(mCRPC). In one embodiment, the CRPC is non-metastatic castrationresistant prostate cancer (nmCRPC). In one embodiment, the nmCRPC ishigh-risk nmCRPC. In another embodiment, the compound is any one ofcompounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, or 300-308. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT).

In one embodiment, this invention provides a method of treating prostatecancer or delaying the progression of prostate cancer comprisingadministering a SARD compound of this invention. In one embodiment, thisinvention provides a method of preventing and/or treating the recurrenceof prostate cancer comprising administering a SARD compound of thisinvention. In another embodiment, the prostate cancer is castrationresistant prostate cancer (CRPC). In another embodiment, the CRPC ismetastatic CRPC (mCRPC). In one embodiment, the CRPC is non-metastaticcastration resistant prostate cancer (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, this invention provides a method of increasing thesurvival of a subject having prostate cancer, advanced prostate cancer,castration resistant prostate cancer or metastatic castration resistantprostate cancer or non-metastatic castration resistant prostate canceror high-risk non metastatic castration resistant prostate cancer,comprising administering a compound of this invention. In anotherembodiment, administering a compound of this invention in combinationwith LHRH analogs, reversible antiandrogens (such as bicalutamide,flutamide, or enzalutamide), anti-estrogens, estrogens (such asestradiol, ethinyl estradiol, or capesaris), anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, selectiveandrogen receptor modulators (SARMs) or agents acting through othernuclear hormone receptors. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In one embodiment, the compound is acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orany one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308.

The term “advanced prostate cancer” refers to metastatic cancer havingoriginated in the prostate, and having widely metastasized to beyond theprostate such as the surrounding tissues to include the seminal vesiclesthe pelvic lymph nodes or bone, or to other parts of the body. Prostatecancer pathologies are graded with a Gleason grading from 1 to 5 inorder of increasing malignancy. In another embodiment, patients withsignificant risk of progressive disease and/or death from prostatecancer should be included in the definition and that any patient withcancer outside the prostate capsule with disease stages as low as IIBclearly has “advanced” disease. In another embodiment, “advancedprostate cancer” can refer to locally advanced prostate cancer.

Men with advanced prostate cancer often receive treatment to block theproduction of androgens, which are male sex hormones that may helpprostate tumors grow. However, prostate cancers that initially respondto antiandrogen therapy eventually develop the ability to grow withoutandrogens. Such cancers are often referred to as hormone refractory,androgen independent, or castration resistant.

In one embodiment, the advanced prostate cancer is castration resistantprostate cancer.

The term “castration resistant prostate cancer” (CRPC) refers toadvanced prostate cancer that is worsening or progressing while thepatient remains on ADT or other therapies to reduce testosterone, orprostate cancer which is considered hormone refractory, hormone naïve,androgen independent or chemical or surgical castration resistant. Inanother embodiment, CRPC is a result of AR activation by intracrineandrogen synthesis. In another embodiment, CRPC is a result ofexpression of AR splice variants (AR-SV) that lack ligand binding domain(LBD). In another embodiment, CRPC is a result of expression of AR-LBDmutations with potential to resist antagonists. In another embodiment,castration resistant prostate cancer (CRPC) is an advanced prostatecancer which developed despite ongoing ADT and/or surgical castration.In one embodiment, castration resistant prostate cancer is defined asprostate cancer that continues to progress or worsen or adversely affectthe health of the patient despite prior surgical castration, continuedtreatment with gonadotropin releasing hormone agonists (e.g.,leuprolide) or antagonists (e.g., degarelix), antiandrogens (e.g.,bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide),chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel,adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinaseinhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib(Cometrig™, also known as XL184)) or other prostate cancer therapies(e.g., vaccines (sipuleucel-T (Provenge®), GVAX, etc.), herbal (PC-SPES)and lyase inhibitor (abiraterone) as evidenced by increasing or higherserum levels of prostate specific antigen (PSA), metastasis, bonemetastasis, pain, lymph node involvement, increasing size or serummarkers for tumor growth, worsening diagnostic markers of prognosis, orpatient condition.

In one embodiment, castration resistant prostate cancer is defined ashormone naïve prostate cancer.

Many early prostate cancers require androgens for growth, but advancedprostate cancers are in some embodiments, androgen-independent, orhormone naïve. In one embodiment, in men with castration resistantprostate cancer, the tumor cells may have the ability to grow in theabsence of androgens (hormones that promote the development andmaintenance of male sex characteristics).

In one embodiment, the term “androgen deprivation therapy” (ADT) or“traditional androgen deprivation therapy” is directed to orchidectomy(surgical castration) wherein the surgeon removes the testicles. Inanother embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administeringluteinizing hormone-releasing hormone (LHRH) analogs: these drugs lowerthe amount of testosterone made by the testicles. Examples of LHRHanalogs available in the United States include leuprolide (Lupron®,Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), andhistrelin (Vantas®). In another embodiment, the term “androgendeprivation therapy” or “traditional androgen deprivation therapy” isdirected to administering antiandrogens: anti-androgens block the body'sability to use any androgens. Even after orchidectomy or duringtreatment with LHRH analogs, a small amount of androgens is still madeby the adrenal glands. Examples of antiandrogens drugs includeenzalutamide (Xtandi®), apalutamide (Erleada®), flutamide (Eulexin®),bicalutamide (Casodex®), and nilutamide (Nilandron®). In anotherembodiment, the term “androgen deprivation therapy” or “traditionalandrogen deprivation therapy” is directed to administering luteinizinghormone-releasing hormone (LHRH) antagonists such as abarelix(Plenaxis®) or degarelix (Firmagon®) (approved for use by the FDA in2008 to treat advanced prostate cancer). In another embodiment, the term“androgen deprivation therapy” or “traditional androgen deprivationtherapy” is directed to administering 5α-reductase inhibitors such asfinasteride (Proscar®) and dutasteride (Avodart®): 5α-reductaseinhibitors block the body's ability to convert testosterone to the moreactive androgen, 5α-dihydrotestosterone (DHT). In another embodiment,the term “androgen deprivation therapy” or “traditional androgendeprivation therapy” is directed to administering inhibitors oftestosterone biosynthesis such as ketoconazole (Nizoral®). In anotherembodiment, the term “androgen deprivation therapy” or “traditionalandrogen deprivation therapy” is directed to administering estrogenssuch as diethylstilbestrol, ethinyl estradiol, capesaris, or17β-estradiol. In another embodiment, the term “androgen deprivationtherapy” or “traditional androgen deprivation therapy” is directed toadministering 17α-hydroxylase/C17,20 lyase (CYP17A1) inhibitors such asabiraterone (Zytiga®).

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an antiandrogen-resistant prostate cancer.In another embodiment, the antiandrogen is bicalutamide,hydroxyflutamide, flutamide, apalutamide, or enzalutamide.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an abiraterone-resistant prostate cancer.

In one embodiment, this invention provides a method of treating prostatecancer in a subject in need thereof, wherein said subject has ARoverexpressing prostate cancer, castration-resistant prostate cancer,castration-sensitive prostate cancer, AR-V7 expressing prostate cancer,or d567ES expressing prostate cancer, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), or XVIb(2) orany one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, the castration-resistant prostate cancer is ARoverexpressing castration-resistant prostate cancer, F876L mutationexpressing castration-resistant prostate cancer, F876L_T877A doublemutation expressing castration-resistant prostate cancer, AR-V7expressing castration-resistant prostate cancer, d567ES expressingcastration-resistant prostate cancer, and/or castration-resistantprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, the castration-sensitive prostate cancer is F876Lmutation expressing castration-sensitive prostate cancer, F876L_T877Adouble mutation castration-sensitive prostate cancer, and/orcastration-sensitive prostate cancer characterized by intratumoralandrogen synthesis.

In one embodiment, the treating of castration-sensitive prostate canceris conducted in a non-castrate setting, or as monotherapy, or whencastration-sensitive prostate cancer tumor is resistant to enzalutamide,apalutamide, and/or abiraterone.

In one embodiment, this invention provides a method of treating ARoverexpressing prostate cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treatingcastration-resistant prostate cancer in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a selective androgen receptor degrader (SARD) compound, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof, wherein said SARDcompound is represented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308. In oneembodiment, the castration-resistant prostate cancer is ARoverexpressing castration-resistant prostate cancer, F876L mutationexpressing castration-resistant prostate cancer, F876L_T877A doublemutation expressing castration-resistant prostate cancer, AR-V7expressing castration-resistant prostate cancer, d567ES expressingcastration-resistant prostate cancer, and/or castration-resistantprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, this invention provides a method of treatingcastration-sensitive prostate cancer in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a selective androgen receptor degrader (SARD) compound, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof, wherein said SARDcompound is represented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308. In oneembodiment, the castration-sensitive prostate cancer is F876L mutationexpressing castration-sensitive prostate cancer, F876L_T877A doublemutation castration-sensitive prostate cancer, and/orcastration-sensitive prostate cancer characterized by intratumoralandrogen synthesis. In one embodiment, the treating ofcastration-sensitive prostate cancer is conducted in a non-castratesetting, or as monotherapy, or when castration-sensitive prostate cancertumor is resistant to enzalutamide, apalutamide, and/or abiraterone.

In one embodiment, this invention provides a method of treating AR-V7expressing prostate cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating d567ESexpressing prostate cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating breastcancer in a subject in need thereof, wherein said subject has ARexpressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7expressing breast cancer, comprising administering to the subject atherapeutically effective amount of a selective androgen receptordegrader (SARD) compound, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof, wherein said SARD compound is represented by the structure offormula I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), or XVIb(2) or any one ofcompounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, and 300-308.

In one embodiment, this invention provides a method of treating ARexpressing breast cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating AR-SVexpressing breast cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating AR-V7expressing breast cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2), or XVIb(2) or any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hormonal condition in a male in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,wherein said SARD compound is represented by the structure of formula I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2), or XVIb(2) or any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, the condition is hypergonadism, hypersexuality,sexual dysfunction, gynecomastia, precocious puberty in a male,alterations in cognition and mood, depression, hair loss,hyperandrogenic dermatological disorders, pre-cancerous lesions of theprostate, benign prostate hyperplasia, prostate cancer and/or otherandrogen-dependent cancers.

In one embodiment, the terms “treating” or “treatment” includespreventative as well as disorder remitative treatment. In anotherembodiment, “treating” or “treatment” does not include preventative. Theterms “reducing”, “suppressing” and “inhibiting” have their commonlyunderstood meaning of lessening or decreasing, in another embodiment, ordelaying, in another embodiment, or reducing, in another embodiment, theincidence, severity or pathogenesis of a disease, disorder or condition.In embodiment, the term treatment refers to delayed progression of,prolonged remission of, reduced incidence of, or amelioration ofsymptoms associated with the disease, disorder or condition. In oneembodiment, the terms “treating” “reducing”, “suppressing” or“inhibiting” refer to a reduction in morbidity, mortality, or acombination thereof, in association with the indicated disease, disorderor condition. In one embodiment, the term “progression” refers to anincreasing in scope or severity, advancing, growing or becoming worse.The term “recurrence” means, in another embodiment, the return of adisease after a remission. In one embodiment, the methods of treatmentof the invention reduce the severity of the disease, or in anotherembodiment, symptoms associated with the disease, or in anotherembodiment, reduces the levels of biomarkers expressed during disease.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, post-polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in late adolescence to adulthood. Proximal limb and bulbarmuscle weakness results in physical limitations including dependence ona wheelchair in some cases. The mutation results in an extendedpolyglutamine tract at the N-terminal domain of the androgen receptor(polyQ AR). Binding and activation of the polyQ AR by endogeneousandrogens (testosterone and DHT) results in unfolding and nucleartranslocation of the mutant androgen receptor. These steps are requiredfor pathogenesis and results in partial loss of transactivation function(i.e., an androgen insensitivity) and a poorly understood neuromusculardegeneration. Currently there are no disease-modifying treatments butrather only symptom directed treatments. Efforts to target the polyQ ARas the proximal mediator of toxicity by harnessing cellular machinery topromote its degradation hold promise for therapeutic invention.Selective androgen receptor degraders such as those reported herein bindto and degrade a variety of androgen receptors (full length, splicevariant, antiandrogen resistance mutants, etc.), indicating that theyare promising leads for treatment of SBMA. This view is supported by theobservation that peripheral polyQ AR anti-sense therapy rescues diseasein mouse models of SBMA (Cell Reports 7, 774-784, May 8, 2014).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of the Kennedy's disease comprisingadministering therapeutically effective amount of a compound of formulasI, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308.

As used herein, “androgen receptor associated conditions” or “androgensensitive diseases or disorders” are conditions, diseases, or disordersthat are modulated by or whose pathogenesis is dependent upon theactivity of the androgen receptor. The androgen receptor is expressed inmost tissues of the body however it is overexpressed in, inter alia, theprostate and skin. ADT has been the mainstay of prostate cancertreatment for many years, and a SARD may also be useful also in treatingvarious prostate cancers, benign prostatic hypertrophy, prostamegaly,and other maladies of the prostate.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of benign prostatic hypertrophy comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostamegaly comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperproliferative prostatic disorders anddiseases comprising administering a therapeutically effective amount ofa compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, or 300-308.

The effect of the AR on the skin is apparent in the gender dimorphismand puberty related dermatological problems common to teens and earlyadults. The hyperandrogenism of puberty stimulates terminal hair growth,sebum production, and predisposes male teens to acne, acne vulgaris,seborrhea, excess sebum, hidradenitis suppurativa, hirsutism,hypertrichosis, hyperpilosity, androgenic alopecia, male patternbaldness, and other dermatological maladies. Although antiandrogenstheoretically should prevent the hyperandrogenic dermatological diseasesdiscussed, they are limited by toxicities, sexual side effects, and lackof efficacy when topically applied. The SARDs of this invention potentlyinhibit ligand-dependent and ligand-independent AR activation, and haveshort biological half-lives in the serum (in some cases), suggestingthat topically formulated SARDs of this invention could be applied tothe areas affected by acne, seborrheic dermatitis, and/or hirsutismwithout risk of systemic side effects.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne vulgaris comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrhea comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308. In one embodiment, this invention is directed to a method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrheic dermatitis comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hidradenitis supporativa comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hirsutism comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hypertrichosis comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperpilosity comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of alopecia comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In some embodiments, the compounds as described herein and/orcompositions may be used for applications in or treating hair loss,alopecia, androgenic alopecia, alopecia areata, alopecia secondary tochemotherapy, alopecia secondary to radiation therapy, alopecia inducedby scarring or alopecia induced by stress. In one embodiment, “hairloss” or “alopecia” refers to baldness as in the very common type ofmale-pattern baldness. Baldness typically begins with patch hair loss onthe scalp and sometimes progresses to complete baldness and even loss ofbody hair. Hair loss affects both males and females.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgenic alopecia comprisingadministering a therapeutically effective amount of a compound of I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, or 300-308. SARDs of this invention may also be usefulin the treatment of hormonal conditions in females such as precociouspuberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterussyndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, earlymenarche, fibrocystic breast disease, fibroids of the uterus, ovariancysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, and vaginal dryness.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of any hyper-androgenic diseases (for examplepolycystic ovary syndrome (PCOS)) comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, or300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precocious puberty or early pubertycomprising administering a therapeutically effective amount of acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, or 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of dysmenorrhea or amenorrhea comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of multilocular uterus syndrome,endometriosis, hysteromyoma, or abnormal uterine bleeding comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of fibrocystic breast disease, fibroids ofthe uterus, ovarian cysts, or polycystic ovary syndrome comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, or vaginal dryness comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308. SARDS of this invention may also findutility in treatment of sexual perversion, hypersexuality, paraphilias,androgen psychosis, virilization, androgen insensitivity syndromes (AIS)such as complete AIS (CAIS) and partial AIS (PAIS), and improvingovulation in an animal.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of sexual perversion, hypersexuality, orparaphilias comprising administering a therapeutically effective amountof a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308 In one embodiment, this invention isdirected to a method of treating, suppressing, reducing the incidence,reducing the severity, or inhibiting the progression of virilizationcomprising administering a therapeutically effective amount of acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndromescomprising administering a therapeutically effective amount of acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308. In one embodiment, theandrogen insensitivity syndrome is a complete androgen insensitivitysyndrome. In another embodiment, the androgen insensitivity syndrome isa partial androgen insensitivity syndrome.

In one embodiment, this invention is directed to a method of increasing,modulating, or improving ovulation in an animal comprising administeringa therapeutically effective amount of a compound of I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308. SARDs of this invention may also be useful for the treating ofhormone-dependent cancers such as prostate cancer, breast cancer,testicular cancer, ovarian cancer, and urogenital cancer, etc. Further,local or systemic SARD administration may be useful for treatment ofprecursors of hormone dependent cancers such as prostaticintraepithelial neoplasia (PIN) and atypical small acinar proliferation(ASAP).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR related solid tumors. In anotherembodiment, the tumor is hepatocellular carcinoma (HCC). In anotherembodiment, the tumor is bladder cancer. Serum testosterone may bepositively linked to the development of HCC. Based on epidemiologic,experimental observations, and notably the fact that men have asubstantially higher risk of bladder cancer than women, androgens and/orthe AR also play a role in bladder cancer initiation.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of breast cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308. In one embodiment, this invention is directed to a method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of testicular cancer comprising administeringa therapeutically effective amount of a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308. In one embodiment, this invention isdirected to a method of treating, suppressing, reducing the incidence,reducing the severity, or inhibiting the progression of uterine cancercomprising administering a therapeutically effective amount of acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308. In one embodiment, thisinvention is directed to a method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofovarian cancer comprising administering a therapeutically effectiveamount of a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 11-27,30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308. Inone embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of urogenital cancer comprising administeringa therapeutically effective amount of a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precursors of prostate cancer comprisinglocal or systemic administration of a therapeutically effective amountof a compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308. In one embodiment, theprecursor of prostate cancers is prostatic intraepithelial neoplasia(PIN). In another embodiment, the precursor of prostate cancer isatypical small acinar proliferation (ASAP).

Although traditional antiandrogens such as enzalutamide, apalutamide(ARN-509), bicalutamide and flutamide and androgen deprivation therapies(ADT) such as leuprolide were approved for use in prostate cancer, thereis significant evidence that antiandrogens could also be used in avariety of other hormone dependent and hormone independent cancers. Forexample, antiandrogens have been successfully tested in breast cancer(enzalutamide; Breast Cancer Res. (2014) 16(1): R₇), non-small cell lungcancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgeninsensitivity syndrome (PAIS) associated malignancies such as gonadaltumors and seminoma, advanced pancreatic cancer (World J.Gastroenterology 20(29):9229), cancer of the ovary, fallopian tubes, orperitoneum, cancer of the salivary gland (Head and Neck (2016) 38:724-731; ADT was tested in AR-expressing recurrent/metastatic salivarygland cancers and was confirmed to have benefit on progression freesurvival and overall survival endpoints), bladder cancer (Oncotarget 6(30): 29860-29876); Int J. Endocrinol (2015), Article ID 384860),pancreatic cancer, lymphoma (including mantle cell), and hepatocellularcarcinoma. Use of a more potent antiandrogen such as a SARD in thesecancers may treat the progression of these and other cancers. Manyhormonal and non-hormonal cancers may benefit from SARD treatment suchas testicular cancer, uterine cancer, ovarian cancer, urogenital cancer,brain cancer, skin cancer, lymphoma, liver cancer, renal cancer,osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer,non-small cell lung cancer (NSCLC), gastric cancer, colon cancer,perianal adenoma, or central nervous system cancer.

SARDs of this invention may also be useful for the treating othercancers containing AR such as breast, brain, skin, ovarian, bladder,lymphoma, liver, kidney, pancreas, endometrium, lung (e.g., NSCLC)colon, perianal adenoma, osteosarcoma, CNS, melanoma, etc.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of brain cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of skin cancer comprising administering atherapeutically effective amount of a compound of I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of ovarian cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of bladder cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lymphoma comprising administering atherapeutically effective amount of a compound of I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of liver cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of 11-27, 30-46,11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of renal cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of osteosarcoma comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pancreatic cancer comprising administeringa therapeutically effective amount of a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308. In one embodiment, this invention isdirected to a method of treating, suppressing, reducing the incidence,reducing the severity, or inhibiting the progression of endometrialcancer comprising administering a therapeutically effective amount of acompound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lung cancer comprising administering atherapeutically effective amount of a compound of formulas I I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, the lung cancer is non-small cell lung cancer(NSCLC).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a central nervous system cancer comprisingadministering a therapeutically effective amount of a compound offormulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of colon cancer comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of melanoma comprising administering atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

SARDs of this invention may also be useful for the treating ofnon-hormone-dependent cancers. Non-hormone dependent cancers includeliver, salivary duct, etc.

In another embodiment, the SARDs of this invention are used for treatinggastric cancer. In another embodiment, the SARDs of this invention areused for treating salivary duct carcinoma. In another embodiment, theSARDs of this invention are used for treating bladder cancer. In anotherembodiment, the SARDs of this invention are used for treating esophagealcancer. In another embodiment, the SARDs of this invention are used fortreating pancreatic cancer. In another embodiment, the SARDs of thisinvention are used for treating colon cancer. In another embodiment, theSARDs of this invention are used for treating non small cell lungcancer. In another embodiment, the SARDs of this invention are used fortreating renal cell carcinoma.

AR plays a role in cancer initiation in hepatocellular carcinoma (HCC).Therefore, targeting AR may be appropriate treatment for patients withearly stage HCC. In late-stage HCC disease, there is evidence thatmetastasis is suppressed by androgens. In another embodiment, the SARDsof this invention are used for treating hepatocellular carcinoma (HCC).

Locati et al. Head & Neck, 2016, 724-731 demonstrated the use ofandrogen deprivation therapy (ADT) in AR-expressing recurrent/metastaticsalivary gland cancers was confirmed to improve progression freesurvival and overall survival endpoints. In another embodiment, theSARDs of this invention are used for treating salivary gland cancer.

Kawahara et al. Oncotarget, 2015, Vol 6 (30), 29860-29876 demonstratedthat ELK1 inhibition, together with AR inactivation, has the potentialof being a therapeutic approach for bladder cancer. McBeth et al. Int. JEndocrinology, 2015, Vol 2015 1-10 suggested that the combination ofanti-androgen therapy plus glucocorticoids since bladder cancer isbelieved to have an inflammatory etiology. In another embodiment, theSARDs of this invention are used for treating bladder cancer.

Abdominal Aortic Aneurysm (AAA)

An abdominal aortic aneurysm (AAA) is an enlarged area in the lower partof the aorta, the major blood vessel that supplies blood to the body.The aorta, about the thickness of a garden hose, runs from your heartthrough the center of your chest and abdomen. Because the aorta is thebody's main supplier of blood, a ruptured abdominal aortic aneurysm cancause life-threatening bleeding. Depending on the size and the rate atwhich your abdominal aortic aneurysm is growing, treatment may vary fromwatchful waiting to emergency surgery. Once an abdominal aortic aneurysmis found, doctors will closely monitor it so that surgery can be plannedif it's necessary. Emergency surgery for a ruptured abdominal aorticaneurysm can be risky. AR blockade (pharmacologic or genetic) reducesAAA. Davis et al. (J Vasc Surg Vol. 63, Issue 6, p1602-1612.e2) showedthat flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcinepancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% comparedto vehicle (121%). Further AR −/− mice showed attenuated AAA growth(64.4%) compared to wildtype (both treated with elastase).Correspondingly, administration of a SARD to a patient suffering from anAAA may help reverse, treat or delay progression of AAA to the pointwhere surgery is needed.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering a therapeutically effective amount ofthe compound of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-46, 11R, 70-79, 80,90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering a therapeutically effective amount of the compound offormulas I, I(1)-1(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115,130-137, 200-205, and 300-308.

In one embodiment, this invention provides a method of treating asubject suffering from a wound, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a woundin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308.

In one embodiment, this invention provides a method of treating asubject suffering from a burn, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a burnin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the compound is any one of compounds11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137, 200-205, and300-308. Wounds and/or ulcers are normally found protruding from theskin or on a mucosal surface or as a result of an infarction in anorgan. A wound may be a result of a soft tissue defect or a lesion or ofan underlying condition. In one embodiment, the term “wound” denotes abodily injury with disruption of the normal integrity of tissuestructures. The term is also intended to encompass the terms “sore”,“lesion”, “necrosis” and “ulcer”. In one embodiment, the term “sore”refers to any lesion of the skin or mucous membranes and the term“ulcer” refers to a local defect, or excavation, of the surface of anorgan or tissue, which is produced by the sloughing of necrotic tissue.Lesion generally relates to any tissue defect. Necrosis is related todead tissue resulting from infection, injury, inflammation orinfarctions. All of these are encompassed by the term “wound”, whichdenotes any wound at any particular stage in the healing processincluding the stage before any healing has initiated or even before aspecific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso: i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is as: i) small tissue loss due to surgicalincisions, minor abrasions and minor bites, or as ii) significant tissueloss. The latter group includes ischemic ulcers, pressure sores,fistulae, lacerations, severe bites, thermal burns and donor site wounds(in soft and hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

Since the skin is the most exposed part of the body, it is particularlysusceptible to various kinds of injuries such as, e.g., ruptures, cuts,abrasions, burns and frostbites or injuries arising from variousdiseases. Furthermore, much skin is often destroyed in accidents.However, due to the important barrier and physiologic function of theskin, the integrity of the skin is important to the well-being of theindividual, and any breach or rupture represents a threat that must bemet by the body in order to protect its continued existence.

Apart from injuries on the skin, injuries may also be present in allkinds of tissues (i.e. soft and hard tissues). Injuries on soft tissuesincluding mucosal membranes and/or skin are especially relevant inconnection with the present invention.

Healing of a wound on the skin or on a mucosal membrane undergoes aseries of stages that results either in repair or regeneration of theskin or mucosal membrane. In recent years, regeneration and repair havebeen distinguished as the two types of healing that may occur.Regeneration may be defined as a biological process whereby thearchitecture and function of lost tissue are completely renewed. Repair,on the other hand, is a biological process whereby continuity ofdisrupted tissue is restored by new tissues which do not replicate thestructure and function of the lost ones.

The majority of wounds heal through repair, meaning that the new tissueformed is structurally and chemically unlike the original tissue (scartissue). In the early stage of the tissue repair, one process which isalmost always involved is the formation of a transient connective tissuein the area of tissue injury. This process starts by formation of a newextracellular collagen matrix by fibroblasts. This new extracellularcollagen matrix is then the support for a connective tissue during thefinal healing process. The final healing is, in most tissues, a scarformation containing connective tissue. In tissues which haveregenerative properties, such as, e.g., skin and bone, the final healingincludes regeneration of the original tissue. This regenerated tissuehas frequently also some scar characteristics, e.g. a thickening of ahealed bone fracture.

Under normal circumstances, the body provides mechanisms for healinginjured skin or mucosa in order to restore the integrity of the skinbarrier or the mucosa. The repair process for even minor ruptures orwounds may take a period of time extending from hours and days to weeks.However, in ulceration, the healing can be very slow and the wound maypersist for an extended period of time, i.e. months or even years.

Burns are associated with reduced testosterone levels, and hypogonadismis associated with delayed wound healing. In one embodiment, the methodsof this invention, provide for treating a subject suffering from a woundor a burn via the administration of a SARD according to this invention.In one embodiment, the SARD promotes resolving of the burn or wound, orin another embodiment, participates in the healing process of a burn ora wound, or in another embodiment, treats a secondary complication of aburn or wound.

In one embodiment, the treatment of burns or wounds further incorporatesthe use of additional growth factors like epidermal growth factor (EGF),transforming growth factor-α (TGF-α), platelet derived growth factor(PDGF), fibroblast growth factors (FGFs) including acidic fibroblastgrowth factor (α-FGF) and basic fibroblast growth factor (β-FGF),transforming growth factor-β (TGF-β) and insulin like growth factors(IGF-1 and IGF-2), or any combination thereof, which are promoters ofwound healing.

Wound healing may be measured by many procedures known in the art,including wound tensile strength, hydroxyproline or collagen content,procollagen expression, and re-epithelialization. As an example, a SARDas described herein is administered orally or topically, at a dosage ofabout 0.1-1 mg per day. Therapeutic effectiveness is measured aseffectiveness in enhancing wound healing. Enhanced wound healing may bemeasured by known techniques such as decrease in healing time, increasein collagen density, increase in hydroxyproline, reduction incomplications, increase in tensile strength, and increased cellularityof scar tissue.

In one embodiment, the term “treating” and its included aspects, refersto the administration to a subject with the indicated disease, disorderor condition, or in some embodiments, to a subject predisposed to theindicated disease, disorder or condition. The term “predisposed to” isto be considered to refer to, inter alia, a genetic profile or familialrelationship which is associated with a trend or statistical increase inincidence, severity, etc. of the indicated disease. In some embodiments,the term “predisposed to” is to be considered to refer to inter alia, alifestyle which is associated with increased risk of the indicateddisease. In some embodiments, the term “predisposed to” is to beconsidered to refer to inter alia, the presence of biomarkers which areassociated with the indicated disease, for example, in cancer, the term“predisposed to” the cancer may comprise the presence of precancerousprecursors for the indicated cancer.

In some embodiments, the term “reducing the pathogenesis” is to beunderstood to encompass reducing tissue damage, or organ damageassociated with a particular disease, disorder or condition. In anotherembodiment, the term “reducing the pathogenesis” is to be understood toencompass reducing the incidence or severity of an associated disease,disorder or condition, with that in question. In another embodiment, theterm “reducing the pathogenesis” is to be understood to encompassreducing the number of associated diseases, disorders or conditions withthe indicated, or symptoms associated thereto.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of thisinvention, together with a pharmaceutically acceptable carrier ordiluent. A “therapeutically effective amount” as used herein refers tothat amount which provides a therapeutic effect for a given conditionand administration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a male subject. In one embodiment,the present invention encompasses administering the compounds of thepresent invention to a female subject.

This invention provides, in other embodiments, pharmaceutical productsof the compounds described herein. The term “pharmaceutical product”refers, in other embodiments, to a composition suitable forpharmaceutical use (pharmaceutical composition), for example, asdescribed herein.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof containing, for example, one or more pharmaceutically acceptablecarriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

The mode of administration and dosage form are closely related to thetherapeutic amounts of the compounds or compositions which are desirableand efficacious for the given treatment application.

The pharmaceutical compositions containing a compound of this inventioncan be administered to a subject by any method known to a person skilledin the art, such as orally, parenterally, intravascularly,paracancerally, transmucosally, transdermally, intramuscularly,intranasally, intravenously, intradermally, subcutaneously,sublingually, intraperitoneally, intraventricularly, intracranially,intravaginally, by inhalation, rectally, intratumorally, or by any meansin which the composition can be delivered to tissue (e.g., needle orcatheter). Alternatively, topical administration may be desired forapplication to the dermal, ocular or mucosal surfaces. Another method ofadministration is via aspiration or aerosol formulation. Further, inanother embodiment, the pharmaceutical compositions may be administeredtopically to body surfaces, and are thus formulated in a form suitablefor topical administration. Suitable topical formulations include gels,ointments, creams, lotions, drops and the like. For topicaladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like areprepared and applied as solutions, suspensions, or emulsions in aphysiologically acceptable diluent with or without a pharmaceuticalcarrier.

Suitable dosage forms include but are not limited to oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterileadministration, and other dosage forms for systemic delivery of activeingredients. In some applications, formulations suitable for oraladministration are preferred. In some applications, formulationssuitable for topical administration are preferred.

Topical Administration: In a typical embodiment, the compounds offormulas I, I(1)-1(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1),V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2),XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) are administeredtopically. Topical administration is especially appropriate forhirsutism, alopecia, acne and excess sebum. The dose will vary, but as ageneral guideline, the compound will be present in a dermatologicallyacceptable carrier in an amount of from about 0.01 to 50 w/w %, and moretypically from about 0.1 to 10 w/w %. Typically, the dermatologicalpreparation will be applied to the affected area from 1 to 4 timesdaily. “Dermatologically acceptable” refers to a carrier which may beapplied to the skin or hair, and which will allows the drug to diffuseto the site of action. More specifically, it refers to a site whereinhibition of androgen receptor or degradation of androgen receptor isdesired.

In a further embodiment, the compounds of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) are used topically to relieve alopecia,especially androgenic alopecia. Androgens have a profound effect on bothhair growth and hair loss. In most body sites, such as the beard andpubic skin, androgens stimulate hair growth by prolonging the growthphase of the hair cycle (anagen) and increasing follicle size. Hairgrowth on the scalp does not require androgens but, paradoxically,androgens are necessary for the balding on the scalp in geneticallypredisposed individuals (androgenic alopecia) where there is aprogressive decline in the duration of anagen and in hair follicle size.Androgenic alopecia is also common in women where it usually presents asa diffuse hair loss rather than showing the patterning seen in men.

While the compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) will most typically be used to alleviate androgenicalopecia, the invention is not limited to this specific condition. Thecompounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) maybe used to alleviate any type of alopecia. Examples of non-androgenicalopecia include alopecia areata, alopecia due to radiotherapy orchemotherapy, scarring alopecia, stress related alopecia, etc. As usedin this application “alopecia” refers to partial or complete hair losson the scalp.

Thus, the compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) can be applied topically to the scalp and hair toprevent, or alleviate balding. Further, the compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) can be applied topically inorder to induce or promote the growth or regrowth of hair on the scalp.

In a further embodiment of the invention, a compound of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) is applied topically in orderto prevent the growth of hair in areas where such hair growth in notdesired. One such use will be to alleviate hirsutism. Hirsutism isexcessive hair growth in areas that typically do not have hair (i.e., afemale face). Such inappropriate hair growth occurs most commonly inwomen and is frequently seen at menopause. The topical administration ofthe compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) willalleviate this condition leading to a reduction, or elimination of thisinappropriate, or undesired, hair growth.

The compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) mayalso be used topically to decrease sebum production. Sebum is composedof triglycerides, wax esters, fatty acids, sterol esters and squalene.Sebum is produced in the acinar cells of the sebaceous glands andaccumulates as these cells age. At maturation, the acinar cells lyse,releasing sebum into the luminal duct so that it may be deposited on thesurface of the skin.

In some individuals, an excessive quantity of sebum is secreted onto theskin. This can have a number of adverse consequences. It can exacerbateacne, since sebum is the primary food source for Propionbacterium acnes,the causative agent of acne. It can cause the skin to have a greasyappearance, typically considered cosmetically unappealing.

Formation of sebum is regulated by growth factors and a variety ofhormones including androgens. The cellular and molecular mechanism bywhich androgens exert their influence on the sebaceous gland has notbeen fully elucidated. However, clinical experience documents the impactandrogens have on sebum production. Sebum production is significantlyincreased during puberty, when androgen levels are their highest. Thusthe compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2)inhibit the secretion of sebum and thus reduce the amount of sebum onthe surface of the skin. The compounds of formulas I, I(1)-1(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) can be used to treat a variety of dermaldiseases such as acne or seborrheic dermatitis.

In addition to treating diseases associated with excess sebumproduction, the compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1),Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII,XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1),XVIa(2) or XVIb(2) can also be used to achieve a cosmetic effect. Someconsumers believe that they are afflicted with overactive sebaceousglands. They feel that their skin is oily and thus unattractive. Theseindividuals can utilize the compounds of formulas I, I(1)-I(2), Ia-Ie,Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) to decrease the amount of sebum on theirskin. Decreasing the secretion of sebum will alleviate oily skin inindividuals afflicted with such conditions.

The compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) ofthis invention will typically be administered topically. As used herein,topical refers to application of the compounds of formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) (and optional carrier) directly to the skinand/or hair. The topical composition according to the present inventioncan be in the form of solutions, lotions, salves, creams, ointments,liposomes, sprays, gels, foams, roller sticks, and any other formulationroutinely used in dermatology.

Thus, a further embodiment relates to cosmetic or pharmaceuticalcompositions, in particular dermatological compositions, which compriseat least one of the compounds corresponding to formulas I, I(1)-I(2),Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2), IXa-IXj, X,XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1),XVIb(1), XVIa(2) or XVIb(2) above. Such dermatological compositions willcontain from 0.001% to 10% w/w % of the compounds in admixture with adermatologically acceptable carrier, and more typically, from 0.1 to 5w/w % of the compounds. Such compositions will typically be applied from1 to 4 times daily. The reader's attention is directed to Remington'sPharmaceutical Science, Edition 17, Mark Publishing Co., Easton, Pa. fora discussion of how to prepare such formulations.

The compositions according to the invention can also consist of solidpreparations constituting cleansing soaps or bars. These compositionsare prepared according to the usual methods.

The compounds of formulas I, I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2),II-VIII, II(1), V(1)-V(2), IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV,XIV(1)-XIV(2), XV, XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) canalso be used for the hair in the form of aqueous, alcoholic oraqueous-alcoholic solutions, or in the form of creams, gels, emulsionsor mousses, or alternatively in the form of aerosol compositions alsocomprising a propellant under pressure. The composition according to theinvention can also be a hair care composition, and in particular ashampoo, a hair-setting lotion, a treating lotion, a styling cream orgel, a dye composition, a lotion or gel for preventing hair loss, etc.The amounts of the various constituents in the dermatologicalcompositions according to the invention are those conventionally used inthe fields considered.

The medicinal and cosmetics containing the compounds of formulas I,I(1)-I(2), Ia-Ie, Ia(1)-Ie(1), Ia(2)-Ie(2), II-VIII, II(1), V(1)-V(2),IXa-IXj, X, XIa-XIj, XII, XIIIa-XIIIj, XIV, XIV(1)-XIV(2), XV, XVIa,XVIb, XVIa(1), XVIb(1), XVIa(2) or XVIb(2) will typically be packagedfor retail distribution (i.e., an article of manufacture). Such articleswill be labeled and packaged in a manner to instruct the patient how touse the product. Such instructions will include the condition to betreated, duration of treatment, dosing schedule, etc.

Antiandrogens, such as finasteride or flutamide, have been shown todecrease androgen activity or block androgen action in the skin to someextent but suffer from undesirable systemic effects. An alternativeapproach is to topically apply a selective androgen receptor degrader(SARD) compound to the affected areas. In one embodiment, such a SARDcompound would exhibit potent but local inhibition of AR activity. Inanother embodiment, the SARD compound would exhibit potent but localdegradation of AR activity. In another embodiment, the SARD compoundwould not penetrate to the systemic circulation of the subject. Inanother embodiment, the SARD compound would be rapidly metabolized uponentry into the blood, limiting systemic exposure.

To prepare such pharmaceutical dosage forms, the active ingredient maybe mixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration.

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Oral or Parenteral Administration: In preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed.Thus, for liquid oral preparations, such as, for example, suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like. For solid oral preparations such as, for example,powders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Due to their ease in administration,tablets and capsules represent the most advantageous oral dosage unitform. If desired, tablets may be sugar coated or enteric coated bystandard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients, for example, ingredients that aidsolubility or for preservation, may be included. Injectable solutionsmay also be prepared in which case appropriate stabilizing agents may beemployed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitablefor oral administration may be presented as discrete units such ascapsules, cachets, tablets, or lozenges, each containing a predeterminedamount of the active ingredient as, for example, a powder or granules.Optionally, a suspension in an aqueous liquor or a non-aqueous liquidmay be employed, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with, for example, a binder, disintegrant,lubricant, inert diluent, surface active agent, or discharging agent.Molded tablets comprised of a mixture of the powdered active compoundwith a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration may comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery. Administration may for example be intravenous, intra-arterial,intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal(e.g., intraperitoneal), etc., and may be effected by infusion pumps(external or implantable) or any other suitable means appropriate to thedesired administration modality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from, for example, diluents, buffers, flavoring agents,binders, disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

The formulations of the present invention can have immediate release,sustained release, delayed-onset release or any other release profileknown to one skilled in the art.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual. In oneembodiment, the methods of this invention may comprise administration ofa compound of this invention at various dosages. In one embodiment, acompound of this invention is administered at a dosage of 1-3000 mg perday. In additional embodiments, a compound of this invention isadministered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg perday, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg,50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg perday, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mgper day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day,1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day,300-1500 mg per day or 100-1000 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 25 mg per day.In one embodiment, a compound of this invention is administered at adosage of 40 mg per day. In one embodiment, a compound of this inventionis administered at a dosage of 50 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 67.5 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 75 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 80 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of100 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 125 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 250 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 300 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of600 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 1000 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 1500 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 2000 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 2500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of3000 mg per day. In another embodiment, the compound is any one ofcompounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, and 300-308. In one embodiment, the methods of this inventionmay comprise administration of a compound of this invention at variousdosages. In one embodiment, a compound of this invention is administeredat a dosage of 3 mg. In additional embodiments, a compound of thisinvention is administered at a dosage of 10 mg, 30 mg, 40 mg, 50 mg, 80mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg. In anotherembodiment, the compound is any one of compounds 11-27, 30-46, 11R,70-79, 80, 90-98, 100-115, 130-137, 200-205, and 300-308.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 0.1 mg/kg/day. In additional embodiments, a compound of thisinvention is administered at a dosage between 0.2 to 30 mg/kg/day, or0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.

In one embodiment, the methods of this invention provide for the use ofa pharmaceutical composition comprising a compound of formulas I,I(1)-I(2), Ia-Id, Ia(1)-Id(1), Ia(2)-Id(2), II-VIII, II(1), V(1)-V(2),IXa-IXh, X, XIa-XIh, XII, XIIIa-XIIIh, XIV, XIV(1)-XIV(2), and XV or anyone of compounds 11-27, 30-46, 11R, 70-79, 80, 90-98, 100-115, 130-137,200-205, and 300-308. In a certain embodiment, the pharmaceuticalcomposition is a solid dosage form. In another embodiment, thepharmaceutical composition is a tablet. In another embodiment, thepharmaceutical composition is a capsule. In another embodiment, thepharmaceutical composition is a solution. In another embodiment, thepharmaceutical composition is a transdermal patch.

In one embodiment, use of a compound of this invention or a compositioncomprising the same, will have utility in inhibiting, suppressing,enhancing or stimulating a desired response in a subject, as will beunderstood by one skilled in the art. In another embodiment, thecompositions may further comprise additional active ingredients, whoseactivity is useful for the particular application for which the compoundof this invention is being administered.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight, genetics and/or response of the particularindividual.

In some embodiments, any of the compositions of this invention willcomprise a compound of this invention, in any form or embodiment asdescribed herein. In some embodiments, any of the compositions of thisinvention will consist of a compound of this invention, in any form orembodiment as described herein. In some embodiments, of the compositionsof this invention will consist essentially of a compound of thisinvention, in any form or embodiment as described herein. In someembodiments, the term “comprise” refers to the inclusion of theindicated active agent, such as the compound of this invention, as wellas inclusion of other active agents, and pharmaceutically acceptablecarriers, excipients, emollients, stabilizers, etc., as are known in thepharmaceutical industry. In some embodiments, the term “consistingessentially of” refers to a composition, whose only active ingredient isthe indicated active ingredient, however, other compounds may beincluded which are for stabilizing, preserving, etc. the formulation,but are not involved directly in the therapeutic effect of the indicatedactive ingredient. In some embodiments, the term “consisting essentiallyof” may refer to components which facilitate the release of the activeingredient. In some embodiments, the term “consisting” refers to acomposition, which contains the active ingredient and a pharmaceuticallyacceptable carrier or excipient.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention. In one embodiment, the compounds are a free base, free acid,non charged or non-complexed compound.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1

Synthesis of Indole/Pyrrolo-Pyridine SARD Compounds of this Invention

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)

D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath. The resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The temperature of the mixture was kept at 10-11° C. during the additionof the methacryloyl chloride. After stirring (3 h, room temperature(RT)), the mixture was evaporated in vacuo at a temperature at 35-45° C.to remove acetone. The resulting solution was washed with ethyl etherand was acidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite®, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (Marhefka, C. A.; Moore, B. M., 2nd; Bishop, T. C.; Kirkovsky, L.;Mukherjee, A.; Dalton, J. T.; Miller, D. D. Homology modeling usingmultiple molecular dynamics simulations and docking studies of the humanandrogen receptor ligand binding domain bound to testosterone andnonsteroidal ligands. J Med Chem 2001, 44, 1729-40: mp 102.5-103.5° C.);the NMR spectrum of this compound demonstrated the existence of tworotamers of the title compound. ¹H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the secondrotamer (totally 2H for both rotamers, vinyl CH₂), 4.48-4.44 for thefirst rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for bothrotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12(1H, CH), 1.97-1.72 (m, 6H, CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δfor major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7,19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0,22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508,1459, 1369, 1348, 1178 cm⁻¹; [α]_(D) ²⁶+80.8° (c=1, MeOH); Anal. Calcd.for C₉H₁₃NO₃: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the(2R)-1-methacryloylpyrrolidin-2-carboxylic acid (2) (16.1 g, 88 mmol) in70 mL of DMF under argon at RT, and the resulting mixture was stirred 3days. The solvent was removed in vacuo, and a yellow solid wasprecipitated. The solid was suspended in water, stirred overnight at RT,filtered, and dried to give 18.6 g (81%) (smaller weight when dried˜34%) of the titled bromolactone (3) as a yellow solid: mp 158.1-160.3°C.; ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH atthe chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C 41.24, H 4.61, N 5.34. Found: C 41.46, H 4.64, N 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4)

A mixture of bromolactone (3) (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite®, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.;¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d,J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500(COOH), 1730 (C═O), 1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D)²⁶+10.5° (c=2.6, MeOH); Anal. Calcd. for C₄H₇BrO₃: C 26.25, H 3.86.Found: C 26.28, H 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4) (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere.The resulting mixture was stirred for 3 h under the same condition. Tothis was added Et₃N (39.14 g, 0.39 mol) and stirred for 20 min under thesame condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g,0.21 mol), 400 mL of THF were added and then the mixture was allowed tostir overnight at RT. The solvent was removed under reduced pressure togive a solid which was treated with 300 mL of H₂O, extracted with EtOAc(2×400 mL). The combined organic extracts were washed with saturatedNaHCO₃ solution (2×300 mL) and brine (300 mL). The organic layer wasdried over MgSO₄ and concentrated under reduced pressure to give a solidwhich was purified from column chromatography using CH₂Cl₂/EtOAc (80:20)to give a solid. This solid was recrystallized from CH₂Cl₂/hexane togive 55.8 g (73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8) as a light-yellow solid. M.p. 134.0-136.5° C.; ¹H NMR (CDCl₃/TMS) δ1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d, J=10.8 Hz, 1H, CH₂), 4.05(d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1,8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH).Calculated Mass: 349.99, [M−H]⁻ 349.0.

Structures of Compounds Synthesized with Different Substituents: (R)- or(S)—N-(4-cyano-3-(trifluoromethyl)-phenyl)-3-(Substituted-1H-indol-1-yl)-2-hydroxy-2-methylpropanamides(11-27, 11R, 30-32, and 80)

Compounds 11-27, 11R, 30-32, and 80 were prepared by the generalprocedures as shown in Scheme 1 or Scheme 2, or Example 2. 11R wassynthesized by same procedures as the other compounds but usingL-proline instead of D-proline as a starting material. And also, 19 wasisolated from the synthetic product of 11 as a by-product.

General Synthetic Procedure of Compounds 11-27, 11R, 30-32, and 80.

Step 1. Preparation of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(10) in THF: A mixture of hydroxylbromide 8 (1.0 g, 2.84 mmol) andpotassium carbonate (790 mg, 5.70 mmol) in 60 mL acetone was heated toreflux for 30 min. After complete conversion of starting bromide 8 todesired epoxide 10 as monitored by TLC, the solvent was evaporated underreduced pressure to give yellowish residue, which was poured into 20 mLof anhydrous EtOAc. The solution was filtered through Celite® pad toremove K₂CO₃ residue and condensed under reduced pressure to give ayellowish solid of epoxide 10, which was dissolved in 5 mL of anhydrousTHF to prepare a solution of epoxide 10 in THF. The resulting solutionwas directly used as next reactant without analysis.

Step 2. NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) wasadded in 30 mL of anhydrous THF solvent into a 100 mL dried two neckedround bottom flask equipped with a dropping funnel and substitutedindole/pyrrolo-pyridine (2.84 mmol) was added to the solution underargon atmosphere in ice-water bath, and the resulting solution wasstirred for 30 min in an ice-water bath. Into the flask, the preparedsolution of epoxide 10 (2.84 mmol in THF) was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at RT. After adding 1 mL of H₂O (1N HCl in case for compound15), the reaction mixture was condensed under reduced pressure, and thendispersed into 50 mL of EtOAc, washed with 50 mL (×2) water, brine,dried over anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography as an eluent EtOAc/hexane, andthen the condensed compounds were then recrystallized in EtOAc/hexane togive any one of the target products 11-27, 11R, 30-32, and 80.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(11): Yield 68%; White solid. MS (ESI): 404.0 [M−H]⁻; 428.2 [M+Na]⁺; mp147.5-148.9° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.77 (bs, 1H, NH), 7.90 (d,J=1.7 Hz, 1H), 7.78-7.76 (m, 2H), 7.38 (dd, J=9.0, 4.2 Hz, 1H), 7.23(dd, J=9.3, 2.5 Hz, 1H), 7.19 (d, J=3.2 Hz, 1H), 6.98 (dt, J=9.0, 2.5Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.38 (d,J=14.8 Hz, 1H), 2.49 (bs, 1H, OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-nitro-1H-indol-1-yl)propanamide(12): Yield 41%; Yellowish solid; mp 152.9-154.8° C.; MS (ESI): 430.9[M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.88 (bs, 1H), 8.04 (d, J=1.6 Hz, 1H),7.89 (s, 1H), 7.79-7.75 (m, 3H), 7.31 (m, 1H), 7.26 (m, 2H), 4.69 (d,J=14.8 Hz, 1H), 4.42 (d, J=14.8 Hz, 1H), 2.43 (bs, 1H, OH), 1.63 (s,3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-methyl-1H-indol-1-yl)propanamide(13): Yield 59%; Yellowish solid: mp 148.6-150.2° C.; MS (ESI): 400.0[M−H]⁻; 424.2 [M+Na]⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.72 (bs, 1H), 7.86 (d,J=2.0 Hz, 1H), 7.78 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 6.84 (dd, J=21.2,3.2 Hz, 1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.63(d, J=14.8 Hz, 1H), 4.31 (d, J=14.8 Hz, 1H), 3.82 (s, 3H), 2.51 (s, 1H,OH), 1.60 (s, 3H).

(S)-3-(5-Cyano-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(14): Yield 54%; White solid: MS (ESI): 411.0 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.85 (bs, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.80-7.73(m, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (m, 1H),6.59 (d, J=3.2 Hz, 1H), 4.68 (d, J=14.8 Hz, 1H), 4.40 (d, J=14.8 Hz,1H), 2.94 (bs, 1H, OH), 1.64 (s, 3H).

(S)-1-(3-((4-Cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-indole-3-carboxylicacid (15): Yield 31%; Light yellowish solid: MS (ESI): 429.9 [M−H]⁻; ¹HNMR (CDCl₃, 400 MHz) δ 9.10 (bs, 1H), 8.11 (m, 1H), 8.01 (s, 1H), 7.91(m, 2H), 7.84 (d, J=1.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.51-7.49 (m, 1H),7.22-7.20 (m, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H),2.94 (s, 1H, OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(5-methoxy-1H-indol-1-yl)-2-methylpropanamide(16): Yield 53%; Brown solid: MS (ESI): 416.0 [M−H]⁻; 418.2 [M+H]+;440.2 [M+Na]⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.74 (bs, 1H), 7.87 (d, J=2.2Hz, 1H), 7.81-7.75 (m, 2H), 7.30 (d, J=3.2 Hz, 1H), 7.09 (d, J=3.2 Hz,1H), 7.03 (d, J=2.2 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 4.63 (d, J=14.8 Hz,1H), 4.30 (d, J=14.8 Hz, 1H), 3.82 (s, 3H), 2.60 (bs, 1H, OH), 1.62 (s,3H).

(S)-3-(5-Chloro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(17): Yield 62%; White solid: MS (ESI): 420.0 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.85 (bs, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.78 (m, 2H), 7.62 (s,1H), 7.32 (d, J=3.2 Hz, 1H), 7.12 (m, 2H), 6.65 (d, J=3.2 Hz, 1H), 4.65(d, J=14.8 Hz, 1H), 4.31 (d, J=14.8 Hz, 1H), 2.52 (bs, 1H, OH), 1.61 (s,3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-(trifluoromethyl)-1H-indol-1-yl)propanamide(18): Yield 57%; White solid: MS (ESI): 453.9 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.80 (bs, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.75 (m, 2H), 7.51 (d,J=3.2 Hz, 1H), 7.41 (m, 1H), 7.21 (m, 1H), 6.62 (d, J=3.2 Hz, 1H), 4.68(d, J=14.8 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H), 2.49 (s, 1H, OH), 1.61 (s,3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-24S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)-3-(5-fluoro-1H-indol-1-yl)-2-methylpropanamide(19): White solid: MS (ESI): 673.9 [M−H]⁻; 698.2 [M+Na]⁺; ¹H NMR (CDCl₃,400 MHz) δ 9.14 (bs, 1H), 8.62 (bs, 1H), 8.16 (d, J=1.8 Hz, 1H), 8.06(dd, J=8.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H),7.75 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.45 (s, 1H), 7.35(m, 1H), 7.24 (m, 1H), 6.98 (d, J=3.2 Hz, 1H), 6.24 (d, J=3.2 Hz, 1H),4.54 (d, J=14.8 Hz, 1H), 4.36 (d, J=14.8 Hz, 1H), 3.96 (d, J=8.8 Hz,1H), 3.55 (d, J=8.8 Hz, 1H), 2.76 (s, 1H, OH), 1.69 (s, 3H), 1.38 (s,3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-nitro-1H-indol-1-yl)propanamide(20): Yield 47%; Yellowish solid: MS (ESI): 431.0 [M−H]⁻; ¹H NMR(Acetone-d₆, 400 MHz) δ 9.68 (bs, 1H, NH), 8.35 (d, J=2.0 Hz, 1H), 8.16(s, 1H), 8.01 (m, 1H), 7.88-7.81 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.38(d, J=3.4 Hz, 1H), 6.58 (d, J=3.4 Hz, 1H), 5.49 (s, 1H, OH), 4.66 (d,J=14.8 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H), 1.50 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(5-iodo-1H-indol-1-yl)-2-methylpropanamide(21): Yield 48%; MS (ESI) 511.9 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.71(bs, 1H, NH), 7.91 (d, J=1.6 Hz, 1H), 7.74 (m, 2H), 7.43 (dd, J=8.8, 1.6Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.44 (d, J=3.2Hz, 1H), 4.62 (d, J=15.0 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.44 (bs, 1H,OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(22): Yield 48%; MS (ESI) 511.9 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.71(bs, 1H, NH), 7.91 (d, J=1.6 Hz, 1H), 7.74 (m, 2H), 7.43 (dd, J=8.8, 1.6Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.44 (d, J=3.2Hz, 1H), 4.62 (d, J=15.0 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.44 (bs, 1H,OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(23): Yield 48%; White solid; MS (ESI) 404.0 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.79 (bs, 1H, NH), 7.89 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.4 Hz,1H), 7.77 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.4, 5.2 Hz, 1H), 7.14 (dd,J=10.0, 2.0 Hz, 1H), 7.11 (d, J=3.2 Hz, 1H), 6.87 (dt, J=8.8, 2.0 Hz,1H), 6.51 (d, J=3.2 Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.32 (d, J=14.8Hz, 1H), 2.56 (bs, 1H, OH), 1.65 (s, 3H).

(S)-3-(5-Bromo-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(24): Yield; 71%; MS (ESI) 465.1 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.73(bs, 1H, NH), 7.88 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.69 (d, J=1.8 Hz,1H), 7.30 (d, J=8.8 Hz, 1H), 7.24 (m, 1H), 7.24 (dd, J=8.8, 2.0 Hz, 1H),7.13 (d, J=3.2 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 4.39 (d, J=14.8 Hz, 1H),2.60 (bs, 1H, OH), 1.65 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(1H-indol-1-yl)-2-methylpropanamide(27)

Yield 55%; Light brown solid; MS (ESI) 358.9 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.67 (bs, 1H, NH), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (s, 1H),7.71-7.65 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.12(t, J=8.0 Hz, 1H), 7.02 (m, 1H), 6.45 (d, J=3.2 Hz, 1H), 4.58 (d, J=14.8Hz, 1H), 4.30 (d, J=14.8 Hz, 1H), 2.50 (bs, 1H, OH), 1.54 (s, 3H).

Preparation of 30 from 15 (S)-Ethyl1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-indole-3-carboxylate(30)

To a solution of carboxylic acid 15 (200 mg, 0.46 mmol) in absoluteethanol of 10 mL was added dropwise a catalytic amount of c-H₂SO₄ underargon atmosphere. The solution was heated to reflux for 30 min andcooled down to RT. The solution was concentrated under reduced pressureand dispersed in EtOAc and then washed with water. The resultingsolution was dried over anhydrous Na₂SO₄ and purified with flash columnchromatography as an eluent EtOAc/hexane (1/2, v/v) to give the titlecompound.

Yield; 92%; MS (ESI) m/z 458.1 [M−H]⁻; 482.4 [M+Na]⁺; ¹H NMR (400 MHz,CDCl₃) δ 8.86 (bs, 1H, NH), 8.00 (m, 2H), 7.81 (s, 1H), 7.65 (s, 2H),7.46 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 2H), 4.65 (d, J=14.4 Hz, 1H), 4.39(d, J=14.4 Hz, 1H), 4.36 (bs, 1H, OH), 4.23-4.11 (m, 2H), 1.66 (s, 3H),1.35 (t, J=7.2 Hz, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(31)

Yield; 64%; MS (ESI) m/z 418.1 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 8.85(bs, 1H, NH), 7.86 (m, 1H), 7.81-7.74 (m, 2H), 7.29 (dd, J=9.0, 4.0 Hz,1H), 7.14 (dd, J=9.0, 2.4 Hz, 1H), 6.92 (m, 2H), 4.60 (d, J=15.2 Hz,1H), 4.27 (d, J=15.2 Hz, 1H), 2.22 (s, 3H), 1.57 (s, 3H).

(S)-3-(5-Cyano-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(80)

Yield; 67%; MS (ESI) m/z 412.1 [M−H]⁻; 436.1 [M+Na]⁺; ¹H NMR (400 MHz,acetone-d₆) δ 9.84 (bs, 1H, NH), 8.31 (s, 1H), 8.14 (m, 2H), 8.01 (m,1H), 7.81 (d, J=2.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.8 Hz,1H), 5.64 (bs, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.52 (d, J=14.8 Hz, 1H),1.66 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(6-nitro-1H-indol-1-yl)propanamide(32)

Yield; 31%; MS (ESI) m/z 431.1 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 8.87(bs, 1H, NH), 8.53 (m, 1H), 8.01 (dd, J=8.8, 2.0 Hz, 1H), 7.92 (d, J=2.0Hz, 1H), 7.86 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.8 Hz, 1H), 7.43 (d, J=3.0 Hz, 1H), 6.61 (d, J=3.0 Hz, 1H), 4.76 (d,J=14.8 Hz, 1H), 4.48 (d, J=14.8 Hz, 1H), 3.14 (s, 1H, OH), 1.74 (s, 3H).

(R)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(11R): 11R was synthesized by the same procedures as the other compoundsbut using L-proline instead of D-proline as a starting material.

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 20mL of anhydrous THF solvent into a 100 mL dried two necked round bottomflask equipped with a dropping funnel. 5-Fluoroindole (390 mg, 2.84mmol) was added to the solution under argon atmosphere in ice-waterbath, and the resulting solution was stirred for 30 min in an ice-waterbath. Into the flask, epoxide 10R (2.84 mmol in THF) was added through adropping funnel under argon atmosphere in an ice-water bath and stirredovernight at RT. After adding 1 mL of H₂O, the reaction mixture wascondensed under reduced pressure, and then dispersed into 50 mL ofEtOAc, washed with 50 mL (×2) water, brine, dried over anhydrous MgSO₄,and evaporated to dryness. The mixture was purified with flash columnchromatography as an eluent EtOAc/hexane, and then the condensedcompounds were then recrystallized in EtOAc/hexane to give a targetproduct 11R.

Yield 69%; White solid. MS (ESI): 404.1 [M−H]⁻; 428.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 8.69 (bs, 1H, NH), 7.80 (d, J=1.2 Hz, 1H), 7.71-7.66(m, 2H), 7.29-7.26 (m, 2H), 7.14 (dd, J=9.2, 2.4 Hz, 1H), 7.09 (d, J=3.2Hz, 1H), 6.86 (dt, J=9.0, 2.5 Hz, 1H), 6.39 (d, J=3.2 Hz, 1H), 4.56 (d,J=14.8 Hz, 1H), 4.26 (d, J=14.8 Hz, 1H), 2.51 (bs, 1H, OH), 1.54 (s,3H).

Example 2 Synthesis of Benzimidazole and Indazole SARD Compounds of thisInvention

(S)—N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(5-fluoro-benzoimidazol-1-yl)-2-hydroxy-2-methyl-propionamide(C₁₉H₁₄F₄N₄O₂) (70)

To a solution of 5-fluoro-1H-benzoimidazole (0.50 g, 0.00367 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.44g, 0.011 mol). After addition, the resulting mixture was stirred for 2h.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(1.29 g, 0.00367 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford 0.17 g of the desiredcompound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H, NH), 8.31 (d, J=17.2 Hz, 1H,ArH), 8.16-8.05 (m, 3H, ArH), 7.62-7.56 (m, 1H, ArH), 7.44 (dd, J=9.60Hz, J=2.4 Hz, 1H, ArH), 7.04 (dd, J=9.60 Hz, J=2.4 Hz, 1H, ArH), 6.49(s, 1H, OH), 4.65 (d, J=5.6 Hz, 1H, CH), 4.62 (d, J=5.6 Hz, 1H, CH),1.47 (s, 3H, CH₃). Mass (ESI, Negative): 404.8[M−H]⁻; (ESI, Positive):429.0[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-((S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)-3-(5-fluoro-1H-benzo[d]imidazol-1-yl)-2-methylpropanamide(C₃₁H₂₃F₇N₆O₄) (72)

This byproduct was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford 50 mg of the titledcompound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, NH), 9.64 (s, 1H, NH), 8.31(d, J=17.2 Hz, 1H, ArH), 8.33-8.30 (m, 1H, ArH), 8.11-7.86 (m, 6H, ArH),7.54-7.52 (m, 1H, ArH), 7.35-7.33 (m, 1H, ArH), 6.77-6.73 (m, 1H, ArH),6.31 (s, 1H, OH), 4.66-4.63 (m, 1H, CH), 4.50-4.44 (m, 1H, CH),3.83-3.82 (m, 1H, CH), 3.66-3.64 (m, 1H, CH), 1.54 (s, 3H, CH₃), 1.34(s, 3H, CH₃). Mass (ESI, Negative): 675.0[M−H]⁻; (ESI, Positive):699.3[M+Na]⁺.

To a solution of 5,6-difluoro-1H-benzoimidazole (0.23 g, 0.00148 mol) inanhydrous THF (10 mL), which was cooled in an dry-ice acetone bath underan argon atmosphere, was added LDA (2.0 M in THF, 1.11 mL, 0.0022 mol).After addition, the resulting mixture was stirred for 2 h.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.40 g, 0.00148 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford the desired compound aswhite solid.

(S)—N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(5,6-difluoro-benzoimidazol-1-yl)-2-hydroxy-2-methyl-propionamide(C₁₉H₁₃F₅N₄O₂) (73)

¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H, NH), 8.25 (d, J=2.0 Hz, 1H,ArH), 8.21 (s, 1H, ArH), 8.14 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.06(d, J=8.8 Hz, 1H, ArH), 7.43-7.40 (m, 1H, ArH), 7.26-7.19 (m, 1H, ArH),6.51 (s, 1H, OH), 4.65 (d, J=14.8 Hz, 1H, CH), 4.41 (d, J=14.8 Hz, 1H,CH), 1.42 (s, 3H, CH₃). Mass (ESI, Negative): 422.7 [M−H]⁻; (ESI,Positive): 447.0 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-hydroxy-2-methylpropanamide(C₁₉H₁₃F₅N₄O₂) (74)

¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H, NH), 8.36 (d, J=2.0 Hz, 1H,ArH), 8.17 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 8.07(d, J=8.4 Hz, 1H, ArH), 7.44-7.41 (m, 1H, ArH), 7.21-7.14 (m, 1H, ArH),6.54 (s, 1H, OH), 4.62 (d, J=14.4 Hz, 1H, CH), 4.52 (d, J=14.4 Hz, 1H,CH), 1.41 (s, 3H, CH₃). Mass (ESI, Negative): 422.7[M−H]⁻; (ESI,Positive): 447.0[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₉H₁₄F₄N₄O₂) (75)

To a solution of 7-fluoro-benzimidazole (0.30 g, 0.0022 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.132g, 0.00331 mol). After addition, the resulting mixture was stirred fortwo hours.(R)-3-Bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide(0.77 g, 0.0022 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using methylenechloride and methanol (19:1) as eluent to afford 0.18 g of the titledcompound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H, NH), 8.39 (d, J=2.0 Hz, 1H,ArH), 8.21 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 8.08(d, J=8.8 Hz, 1H, ArH), 7.46 (d, J=8.0 Hz, 1H, ArH), 7.16-7.10 (m, 1H,ArH), 7.05-7.00 (m, 1H, ArH), 6.52 (s, 1H, OH), 4.64-4.56 (m, 2H, CH),1.35 (s, 3H, CH₃). Mass (ESI, Negative): 404.8[M−H]⁻.

Synthesis of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(76) &(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(75)

Under an argon atmosphere, 1.5 mL of lithium bis(trimethylsilyl)amide inTHF (1.5 mmol, Aldrich, 1 M solution in THF) was slowly added to asolution of 4-fluoro-1H-benzo[d]imidazole (136 mg, 1 mmol) in THF (10mL) at −78° C. and stirred for 30 min at the same temperature. Asolution of 8R (318 mg, 1 mmol) in 5 mL of THF was added dropwise to thesolution. The reaction mixture was stirred at the same temperature for30 min and stirred overnight at RT, quenched by an addition of sat.NH₄C₁ solution. The mixture was concentrated under reduced pressure anddispersed into excess EtOAc and dried over Na₂SO₄, concentrated andpurified by flash column chromatography (EtOAc/hexane) to give thetarget compound give total 70% yield of 76 (30%, 120.3 mg) and 75 (40%,163.1 mg) as white solid.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(76)

HRMS (ESI) m/z calcd for C₁₉H₁₅F₄N₄O₂: 407.1131 [M+H]⁺. Found: 407.1137[M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.10 (bs, 1H, NH), 8.11 (s, 1H), 7.79 (s, 1H),7.75-7.71 (m, 2H), 7.38 (m, 1H), 7.31-7.26 (m, 1H), 6.81 (t, J=8.0 Hz,1H), 6.01 (bs, 1H, OH), 4.93 (d, J=14.0 Hz, 1H), 4.44 (d, J=14.0 Hz,1H), 1.53 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−62.22, −117.60.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(75)

HRMS (ESI) m/z calcd for C₁₉H₁₅F₄N₄O₂: 407.1131. Found: 407.1126 [M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.14 (bs, 1H, NH), 8.08 (s, 1H), 7.96 (s, 1H),7.82 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H),7.42 (d, J=8.8 Hz, 1H), 7.23 (m, 1H), 7.67 (dd, J=10.0, 7.6 Hz, 1H),6.67 (bs, 1H, OH), 4.96 (d, J=13.6 Hz, 1H), 4.54 (d, J=13.6 Hz, 1H),1.54 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−62.22, −116.56.

2-Dimensional nuclear Overhauser effect (NOE) spectroscopy (NOESY):NOESY was used to assign the correct chemical structures to these twoisomers. 76 demonstrated an NOEs between the aromatic proton located atthe 7-position of the benzo[d]imidazole ring (annotated as H) and themethylene protons (annotated as H₁ and H₂),

indicating that the point of attachment to the benzo[d]imidazole ringmust be the 1-position. Whereas for 75, an NOE was observed between2-position aromatic proton of the benzo[d]imidazole ring (annotated asH) and the methylene protons (annotated as H₁ and H₂),

indicating that the point of attachment to the benzo[d]imidazole ringmust be the 1-position (opposite nitrogen as for 76) hence fluorine issubstituted at the 7-position of the benzo[d]imidazole ring and thisproduct is identical to the other 75 reported above. The variable NMRvalues are due to the different NMR solvents used.

Synthesis of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propanamide(77) and(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propanamide(78)

Under an argon atmosphere, 2.0 mL of lithium bis(trimethylsilyl)amide inTHF (2 mmol, Aldrich, 1 M solution in THF) was slowly added to asolution of 4-(trifluoromethyl)-1H-benzo[d]imidazole (186 mg, 1 mmol) inTHF (10 mL) at −78° C. and stirred for 30 min at that temperature. Asolution of R-bromo amide 8R (351 mg, 1 mmol) in 5 mL of THF was addeddropwise to the solution. The reaction mixture was stirred at the sametemperature for 30 min and stirred overnight at RT, quenched by anaddition of sat. NH₄C₁ solution. The mixture was concentrated underreduced pressure and dispersed into excess EtOAc and dried over Na₂SO₄,concentrated and purified by flash column chromatography (EtOAc/hexane;1/1 and then EtOAc only) to give 77 and 78 as a white solid.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propanamide(77)

HRMS (ESI) m/z calcd for C₂₀H₁₅F₆N₄O₂: 457.1099 [M+H]⁺. Found: 457.1094[M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.16 (bs, 1H, NH), 8.07 (s, 1H), 9.95 (s, 1H),7.76 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.34 (t,J=7.8 Hz, 1H), 6.37 (bs, 1H, OH), 4.70 (d, J=14.4 Hz, 1H), 4.47 (d,J=14.4 Hz, 1H), 1.58 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−60.52, −62.29.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propanamide(78)

HRMS (ESI) m/z calcd for C₂₀H₁₅F₆N₄O₂: 457.1099 [M+H]⁺. Found: 457.1090[M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.32 (bs, 1H, NH), 8.26 (s, 1H), 8.12 (d,J=2.0 Hz, 1H), 7.99 (dd, J=8.6, 2.0 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H),7.77 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H),5.91 (bs, 1H, OH), 4.94 (d, J=15.2 Hz, 1H), 4.67 (d, J=15.2 Hz, 1H),1.48 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−55.42, 62.14.

Synthesis of(S)—N-(3-chloro-4-cyanophenyl)-3-(4-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(79)

To a dry, nitrogen-purged 50 mL round-bottom flask,(R)-3-bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(318 mg, 1 mmol), 4-fluoro-1H-benzo[d]imidazole (136 mg, 1 mmol) andK₂CO₃ (415 mg, 3 mmol) were dissolved into 10 mL of DMF. The mixture washeated up to 80° C. for 3 h. The resulting mixture was cooled down toRT. The volume of the mixture was reduced under reduced pressure andpoured into water, and extracted with ethyl acetate (3 times). Theorganic layer was dried over anhydrous MgSO₄, concentrated and purifiedby flash column chromatography (ethyl acetate only, rf=0.31) on silicagel to produce 79 (38%).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(79)

HRMS (ESI) m/z calcd for C₁₈H₁₅ClF₄N₄O₂: 373.0868 [M+H]⁺. Found:373.0878 [M+H]⁺;

¹H NMR (Acetone-d₆, 400 MHz) δ 9.77 (bs, 1H, NH), 8.16 (d, J=1.6 Hz,1H), 8.04 (s, 1H), 7.83 (dd, J=8.4, 1.6 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H),7.44 (d, J=4.8 Hz, 1H), 7.18 (m, 1H), 6.99 (dd, J=11.6, 8.0 Hz, 1H),5.83 (bs, 1H, OH), 4.78 (d, J=14.4 Hz, 1H), 4.69 (d, J=14.4 Hz, 1H),1.56 (s, 3H).

Synthesis of Indazole SARDs

To a solution of substituted-1H-indazole (0.00148 mol; e.g.,5-fluoro-1H-indazole for 90) in anhydrous THF (10 mL), which was cooledin an dry-ice acetone bath under an argon atmosphere, was added LDA (2.0M in THF, 1.11 mL, 0.0022 mol). After addition, the resulting mixturewas stirred for 2 h.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.40 g, 0.00148 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford the desired compound aswhite solid.

Example 3 Synthesis of Quinoline, Isoquinoline, and Indoline SARDCompounds of this Invention Quinoline Compounds

Isoquinoline Compounds

Indoline Compounds

General Procedure: Method A: General Scheme for the Synthesis ofIndoline, Quinoline and Isoquinoline Derivatives

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2R)

D-Proline (1R) (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOHand cooled in an ice bath; the resulting alkaline solution was dilutedwith acetone (71 mL). An acetone solution (71 mL) of methacryloylchloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) weresimultaneously added over 40 min to the aqueous solution of D-proline inan ice bath. The temperature of the mixture was kept at 10-11° C. duringthe addition of the methacryloyl chloride. After stirring (3 h, roomtemperature (RT)), the mixture was evaporated in vacuo at a temperatureat 35-45° C. to remove acetone. The resulting solution was washed withethyl ether and was acidified to pH 2 with concentrated HCl. The acidicmixture was saturated with NaCl and was extracted with EtOAc (100 mL×3).The combined extracts were dried over Na₂SO₄, filtered through Celite®,and evaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (Marhefka, C. A.; Moore, B. M., 2nd; Bishop, T. C.; Kirkovsky, L.;Mukherjee, A.; Dalton, J. T.; Miller, D. D. Homology modeling usingmultiple molecular dynamics simulations and docking studies of the humanandrogen receptor ligand binding domain bound to testosterone andnonsteroidal ligands. J Med Chem 2001, 44, 1729-40) mp 102.5-103.5° C.;the NMR spectrum of this compound demonstrated the existence of tworotamers of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer,5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for bothrotamers, vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) forthe second rotamer (totally 1H for both rotamers, CH at the chiralcenter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H,CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3,169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437(OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178cm⁻¹; [α]_(D) ²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C 59.00,H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3R)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the(2R)-1-methacryloylpyrrolidin-2-carboxylic acid (2R) (16.1 g, 88 mmol)in 70 mL of DMF under argon at RT, and the resulting mixture was stirred3 days. The solvent was removed in vacuo, and a yellow solid wasprecipitated. The solid was suspended in water, stirred overnight at RT,filtered, and dried to give 18.6 g (81%) (smaller weight when dried˜34%) of the titled bromolactone (3R) as a yellow solid: mp 158.1-160.3°C.;

¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4 Hz,1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72(m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474,1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹;[α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C41.24, H 4.61, N 5.34. Found: C 41.46, H 4.64, N 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4R)

A mixture of bromolactone (3R) (18.5 g, 71 mmol) in 300 mL of 24% HBrwas heated at reflux for 1 h. The resulting solution was diluted withbrine (200 mL), and was extracted with ethyl acetate (100 mL×4). Thecombined extracts were washed with saturated NaHCO₃ (100 mL×4). Theaqueous solution was acidified with concentrated HCl to pH=1, which, inturn, was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite®, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d,J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me).

IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O), 1449, 1421, 1380,1292, 1193, 1085 cm⁻¹.

[α]_(D) ²⁶+10.5° (c=2.6, MeOH).

Anal. Calcd. for C₄H₇BrO₃: C 26.25, H 3.86. Found: C 26.28, H 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8R, X═CF₃)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4R) (51.13 g, 0.28 mol) in 300 mL of THF under an argonatmosphere. The resulting mixture was stirred for 3 h under the samecondition. To this was added Et₃N (39.14 g, 0.39 mol) and stirred for 20min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at RT. Thesolvent was removed under reduced pressure to give a solid which wastreated with 300 mL of H₂O, extracted with EtOAc (2×400 mL). Thecombined organic extracts were washed with saturated NaHCO₃ solution(2×300 mL) and brine (300 mL). The organic layer was dried over MgSO₄and concentrated under reduced pressure to give a solid which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8R, X═CF₃) as a light-yellow solid. M.p. 134.0-136.5° C.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M−H]⁻ 349.0.

General Procedure for Preparation of Indoline, Quinoline andIsoquinoline Derivatives (Last Step):

Preparation of LDA solution in THF. To a stirred solution of freshlydistilled diisopropylamine (0.14 mL, 1.2 mmol) in anhydrous 5 mL of THFwas added a solution of n-butyllithium (0.53 mL, 1.32 mmol, 2.5 Msolution in hexane) at −78° C. under argon atmosphere. The preparedsolution of LDA or 2.0 M LDA was slowly warmed to 0° C. and stirred for10 min and cooled again to −78° C.

To the LDA solution was added dropwise a solution of 9 (1.0 mmol) in 5mL of THF for 20 min. The reaction mixture was stirred at the sametemperature for 30 min and quenched by addition of sat. NH₄C₁. Thesolution was concentrated under reduced pressure and dispersed intoexcess EtOAc and dried over Na₂SO₄. The solution was concentrated andthe resulting solid was recrystallized from EtOAc/hexane or DCM/hexaneto give desired compound 10S. The mother liquor was concentrated andpurified by flash column chromatography (EtOAc/hexane) to giveadditional 10S.

Alternative Procedure for Preparation of Indoline Compounds (Last Step):

NaH of 60% dispersion in mineral oil (61 mg, 1.5 mmol) was added in 5 mLof anhydrous THF solvent into a 50 mL dried two necked round bottomflask equipped with a dropping funnel. 5-Fluoroindoline or5-bromoindoline (1.48 mmol) was added to the solution under argonatmosphere in an ice-water bath, and the resulting solution was stirredfor 30 min in an ice-water bath. Into the flask, the prepared solutionof the oxirane:(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide,(1.48 mmol in THF) was added through dropping funnel under argonatmosphere in an ice-water bath and stirred overnight at RT. Afteradding 1 mL of H₂O, the reaction mixture was condensed under reducedpressure, and then dispersed into 20 mL of EtOAc, washed with 20 mL (×2)water, brine, dried over anhydrous Na₂SO₄, and evaporated to dryness.The mixture was purified with flash chromatography (EtOAc/hexane 40%solvent, SIO₂) and afforded the desired products 100 or 102.

(S)-3-(5-Bromoindolin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(100)

Yield 45%; Light brown solid; MS (ESI) 466.3 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 9.17 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.49 (d, J=8.4 Hz,1H), 3.66 (d, J=14.4 Hz, 1H), 3.48 (bs, 1H, OH), 3.47-3.41 (m, 1H), 3.34(q, J=9.2 Hz, 1H), 3.25 (d, J=14.4 Hz, 1H), 3.00-2.91 (m, 2H), 1.56 (s,3H).

(S)-3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (134). Yield; 62%; MS (ESI) m/z481.6 [M−H]; ¹H NMR (400 MHz, CDCl₃) δ 9.19 (bs, 1H, NH), 8.00 (s, 1H),7.97-7.92 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.8, 2.4 Hz, 1H),7.08 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.86 (d, J=15.2 Hz, 1H),3.45 (d, J=15.2 Hz, 1H), 3.21 (t, J=5.4 Hz, 2H), 2.74 (m, 2H), 1.87 (m,2H), 1.60 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(101). Yield; 68%; MS (ESI) m/z 406.0 [M−H]; ¹H NMR (400 MHz, CDCl₃) δ9.21 (bs, 1H, NH), 8.10 (d, J=2.4 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H),7.89 (d, J=8.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.47 (t, J=8.4 Hz, 1H), 6.39(d, J=8.0 Hz, 1H), 3.69 (d, J=14.4 Hz, 1H), 3.53 (bs, 1H, OH), 3.50 (m,1H), 3.40 (q, J=8.0 Hz, 1H), 3.29 (d, J=14.4 Hz, 1H), 3.09 (m, 1H), 2.99(m, 1H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(102). Yield; 75%; MS (ESI) m/z 406.0 [M−H]; ¹H NMR (400 MHz, CDCl₃) δ9.24 (bs, 1H, NH), 8.10 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.8, 2.2 Hz, 1H),7.79 (d, J=8.8 Hz, 1H), 6.83 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (m. 1H), 6.52(dd, J=8.4, 4.0 Hz, 1H), 3.75 (bs, 1H, OH), 3.64 (d, J=14.0 Hz, 1H),3.44 (m, 1H), 3.30 (q, J=9.2 Hz, 1H), 3.22 (d, J=14.0 Hz, 1H), 2.94 (m,2H), 1.56 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydroxy-2-methylpropanamide(135). Yield; 42%; MS (ESI) m/z 420.0 [M−H]; ¹H NMR (400 MHz, CDCl₃) δ9.25 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.4, 2.0 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 6.78-6.69 (m, 1H), 6.77 (m, 3H), 3.88 (d, J=15.2Hz, 1H), 3.82 (bs, 1H, OH), 3.36 (d, J=15.2 Hz, 1H), 3.16 (m, 2H),3.16-2.70 (m, 2H), 1.94-1.83 (m, 2H), 1.56 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropanamide(131). Yield; 43%; MS (ESI) m/z 419.9 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ9.51 (bs, 1H, NH), 8.10 (d, J=1.8 Hz, 1H), 7.95 (dd, J=8.6, 1.8 Hz, 1H),7.79 (d, J=8.6 Hz, 1H), 6.88 (m, 1H), 6.81 (m. 2H), 3.69 (s, 2H), 3.42(d, J=13.2 Hz, 1H), 2.91 (m, 4H), 2.60 (d, J=13.2 Hz, 1H), 2.17 (s, 1H,OH), 1.46 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(105). Yield; 70%; MS (ESI) m/z 405.9 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ9.21 (bs, 1H, NH), 8.10 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 6.98 (t, J=6.8 Hz, 1H), 6.41 (t, J=7.6 Hz, 1H), 3.35 (m, 1H),3.66 (d, J=14.0 Hz, 1H), 3.52 (bs, 1H, OH), 3.47 (m, 1H), 3.41 (q, J=9.2Hz, 1H), 3.24 (d, J=14.0 Hz, 1H), 3.00-2.87 (m, 2H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropanamide(132). Yield; 69%; MS (ESI) 420.0 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.09(bs, 1H, NH), 7.93 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.05 (t,J=8.0 Hz, 1H), 6.86 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 3.71 (s, 2H), 3.42(d, J=13.2 Hz, 1H), 2.91-2.82 (m, 5H), 2.60 (d, J=13.2 Hz, 1H), 1.46 (s,3H).

Example 4 Synthesis of SARD Compounds of this Invention

Method A. General Scheme for Preparation of Indoline, Quinolone andIsoquinoline Derivatives

Preparation of LDA solution in THF: To a stirred solution of freshlydistilled diisopropylamine (0.14 mL, 1.2 mmol) in anhydrous 5 mL of THFwas added a solution of n-butyllithium (0.53 mL, 1.32 mmol, 2.5 Msolution in hexane) at −78° C. under argon atmosphere. The preparedsolution of LDA or commercial 2.0 M LDA was slowly warmed to 0° C. andstirred for 10 min and cooled again to −78° C. To the LDA solution wasadded dropwise a solution of 9 (1.0 mmol) in 5 mL of THF for 20 min. 8Rin THF was added dropwise through dropping funnel under argon atmosphereat −78° C. The reaction mixture was stirred at the same temperature for30 min and quenched by addition of sat. NH₄C₁. The solution wasconcentrated under reduced pressure and dispersed into excess EtOAc anddried over Na₂SO₄. The solution was concentrated and the resulting solidwas recrystallized from EtOAc/hexane or DCM/hexane to give designedcompound 10. The mother liquor was concentrated and purified by flashcolumn chromatography (EtOAc/hexane) to give the 10 additionally.

Method B. Preparation of Indoles and Carbazoles

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 20mL of anhydrous THF solvent into a 100 mL dried two necked round bottomflask equipped with a dropping funnel. Indole (general structure 12,2.84 mmol) was added to the solution under argon atmosphere in ice-waterbath, and the resulting solution was stirred for 30 min at the ice-waterbath. Into the flask, epoxide 11 (2.84 mmol in THF) was added throughdropping funnel under argon atmosphere at the ice-water bath and stirredovernight at RT. After adding 1 mL of H₂O, the reaction mixture wascondensed under reduced pressure, and then dispersed into 50 mL ofEtOAc, washed with 50 mL (×2) water, brine, dried over anhydrous MgSO₄,and evaporated to dryness. The mixture was purified with flash columnchromatography with an eluent of EtOAc/hexane, and then the condensedcompounds were then recrystallized in EtOAc/hexane to give a targetproduct of general structure 13.

(S)—N-(3-Chloro-4-cyanophenyl)-2-methyloxirane-2-carboxamide (EpoxideIntermediate)

Yield 98%;

Light brown solid.

MS (ESI) m/z 235.4 [M−H]⁻.

¹H NMR (CDCl₃, 400 MHz) δ 7.90 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz,1H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 2.99 (s, 2H), 1.67 (s, 3H).

Indole Derivatives(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(33)

To a solution of 5-fluoro-6-phenyl-1H-indole (0.37 g, 0.00175 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.11g, 0.00263 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.47 g, 0.002175 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.83 g(98%) of the titled compound as off-white foam.

¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H, NH), 8.28 (s, 1H, ArH), 8.08(d, J=8.8 Hz, 1H, ArH), 7.96 (d, J=8.8 Hz, 1H, ArH), 7.58 (d, J=6.8 Hz,1H, ArH), 7.49-7.31 (m, 7H, ArH), 6.42 (d, J=3.2 Hz, 1H, ArH), 6.35 (s,1H, OH), 4.61 (d, J=14.4 Hz, 1H, CH), 4.35 (d, J=14.4 Hz, 1H, CH), 1.46(s, 3H, CH₃).

Mass (ESI, Negative): 479.9[M−H]⁻; (ESI, Positive): 504.1[M+Na]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(34) 5-Fluoro-6-phenyl-1H-indole (C₁₄H₁₀FN)

To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄,0.54 g, 0.467 mmol] in 20 mL of ethylene glycol dimethyl ether (DME) wasadded 6-bromo-5-fluoroindole (1.00 g, 4.67 mmol), and the mixture wasstirred for 15 minutes under argon at RT. A solution of phenylboronicacid (0.57 g, 4.67 mmol) in 2-3 mL of ethanol was added and the mixturewas stirred for 10 minutes under the same conditions. A solution ofpotassium carbonate (0.97 g, 7.01 mmol) in 2 mL of water was added toabove mixture and the resulting reaction mixture was heated at refluxfor 3-4 hours under the argon atmosphere. After the end of the reactionwas established by TLC, the reaction was diluted by brine, and extractedwith ethyl acetate. The organic layer was washed with brine, dried withMgSO₄, filtered, and concentrated under vacuum. The product was purifiedby a silica gel column using ethyl acetate and hexane (1:3) as eluent toafford 0.90 g (92% yield) of the titled compound as light brown solid.

To a solution of 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.000947 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.076g, 0.00189 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.30 g, 0.000947 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate.

The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.26 gof the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H, NH), 8.04 (d, J=1.6 Hz, 1H,ArH), 7.80 (d, J=8.8 Hz, 1H, ArH), 7.74 (dd, J=8.2 Hz, J=2.0 Hz, 1H,ArH), 7.62 (d, J=6.4 Hz, 1H, ArH), 7.51-7.44 (m, 4H, ArH), 7.39-7.32 (m,3H, ArH), 6.42 (d, J=3.2 Hz, 1H, ArH), 6.33 (s, 1H, OH), 4.60 (d,J=15.2Hz, 1H, CH), 4.35 (d,J=15.2 Hz, 1H, CH), 1.45 (s, 3H, CH₃).

Mass (ESI, Negative): 445.8[M−H]⁻; (ESI, Positive): 470.0[M+Na]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(6-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(35)

Method B

Yield 67%;

White solid;

MS (ESI) m/z 376.9 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.67 (bs, 1H, NH), 7.79 (d, J=2.0 Hz, 1H),7.56 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 5.4 Hz, 1H), 7.38 (dd, J=8.4,2.0 Hz, 1H), 7.13 (dd, J=10.0, 2.0 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.86(m, 2H), 6.48 (d, J=3.2 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 4.28 (d,J=14.8 Hz, 1H), 2.61 (bs, 1H, OH), 1.60 (s, 3H);

¹⁹F NMR (CDCl₃) δ−120.03.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(36)

Method B

Under argon atmosphere into a 100 mL, dried, two-necked round bottomflask equipped with a dropping funnel in ice-water bath, NaH of 60%dispersion in mineral oil (228 mg, 5.70 mmol) was added in 20 mL ofanhydrous THF solvent into the flask and 4-fluoroindole (390 mg, 2.84mmol) solution in 10 mL of anhydrous THF was added to the solution underthe argon atmosphere in the ice-water bath, and then the resultingsolution was stirred at the ice-water bath. After 30 min, into theflask, a solution of(S)—N-(3-chloro-4-cyanophenyl)-2-methyloxirane-2-carboxamide (2.84 mmolin THF) was added through dropping funnel under argon atmosphere at theice-water bath and stirred overnight at RT. After adding 1 mL of H₂O,the reaction mixture was condensed under reduced pressure, and thendispersed into 50 mL of EtOAc, washed with 50 mL (×2) water, brine,dried over anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography as an eluent EtOAc/hexane, andthen the condensed compounds were then recrystallized in EtOAc/hexane togive a target product, 36.

Yield 73%.

White solid.

MS (ESI) m/z 369.9 [M−H]⁻; HRMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915. Found: 372.0915 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.64 (bs, 1H, NH), 7.81 (s, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.14-7.10(m, 2H), 6.77 (t, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.60 (s, 1H),4.64 (d, J=14.8 Hz, 1H), 4.35 (d, J=14.8 Hz, 1H), 2.48 (bs, 1H, OH),1.60 (s, 3H).

¹³C NMR (acetone-d₆, 100 MHz) δ 174.8, 158.1, 155.7, 144.3, 141.5 (d,J=11.0 Hz), 137.2, 135.5, 130.7, 122.4 (d, J=7.0 Hz), 121.0, 119.3,118.0 (d, J=22.0 Hz), 116.6, 107.9 (t, J=5.0 Hz), 104.4 (d, J=19.0 Hz),97.7, 77.6, 55.0, 24.2. ¹⁹F NMR (CDCl₃, decoupled) δ−121.78.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(37)

Method B

Yield 79%.

White solid.

MS (ESI) m/z 371.0 [M−H]⁻; HRMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915.

Found: 372.0922 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.62 (bs, 1H, NH), 7.80 (d, J=2.0 Hz, 1H),7.56 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 2H), 7.23 (dd, J=9.2, 2.4 Hz, 1H),7.15 (d, J=3.2 Hz, 1H), 7.22 (dt, J=9.2, 2.8 Hz, 1H), 6.47 (d, J=3.2 Hz,1H), 4.63 (d, J=14.8 Hz, 1H), 4.32 (d, J=14.8 Hz, 1H), 2.49 (bs, 1H,OH), 1.60 (s, 3H).

¹⁹F NMR (CDCl₃) δ −124.52.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(3-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(38)

Method B

Yield 68%;

Mp 168.9-170.1° C.

Light Brown solid.

MS (ESI) m/z 369.8 [M−H]⁻; LCMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915. Found:

372.0910 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.66 (bs, 1H, NH), 7.81 (d, J=2.0 Hz, 1H),7.60-7.56 (m, 2H), 7.37 (dd, J=8.4, 2.0 Hz, 2H), 7.23 (m, 1H), 7.12 (t,J=7.4 Hz, 1H), 6.93 (d, J=2.8 Hz, 1H), 4.56 (d, J=15.2 Hz, 1H), 4.27 (d,J=15.2 Hz, 1H), 2.44 (s, 1H, OH), 1.59 (s, 3H). ¹⁹F NMR (CDCl₃)δ−173.91.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(7-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(39)

Method B

Yield 73%.

White solid.

MS (ESI) m/z 370.0 [M−H]⁻.

¹H NMR (CDCl₃, 400 MHz) δ 8.60 (bs, 1H, NH), 8.82 (d, J=2.0 Hz, 1H),7.55 (d, J=8.4 Hz, 1H), 7.37-7.34 (m, 2H), 7.02 (d, J=3.2 Hz, 1H), 7.00(m, 1H), 7.01-6.98 (m, 1H), 6.91 (m, 1H), 6.46 (t, J=2.8 Hz, 1H), 4.68(d, J=15.0 Hz, 1H), 4.62 (d, J=15.0 Hz, 1H), 2.73 (d, J=4.4 Hz, 1H, OH),1.61 (s, 3H). ¹⁹F NMR (CDCl₃) δ−133.54.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-3-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(40)

To a solution of 5-fluoro-3-phenyl-1H-indole (0.50 g, 0.002267 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.24g, 0.005918 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.75 g, 0.002267 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2 to 1:1) as eluent to afford0.43 g of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H, NH), 8.06 (d, J=2.0 Hz, 1H,ArH), 7.86-7.79 (m, 2H, ArH), 7.64 (s, 1H, ArH), 7.62-7.58 (m, 1H, ArH),7.55-7.52 (m, 2H, ArH), 7.50 (dd, J=10.4 Hz, J=2.4 Hz, 1H, ArH),7.43-7.40 (m, 2H, ArH), 7.26-7.22 (m, 1H, ArH), 7.03-6.98 (m, 1H, ArH),6.37 (s, 1H, OH), 4.60 (d, J=14.8 Hz, 1H, CH), 4.38 (d, J=14.8 Hz, 1H,CH), 1.46 (s, 3H, CH₃).

Mass (ESI, Negative): 446.8[M−H]⁻; (ESI, Positive): 448.1248[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-phenyl-1H-indol-1-yl)propanamide(41) Phenyl-1H-indole (C₁₄H₁₁N)

To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄,1.179 g, 1.0212 mmol] in 40 mL of ethylene glycol dimethyl ether (DME)was added 4-bromo-indole (2.00 g, 10.202 mmol), and the mixture wasstirred for 15 minutes under argon at RT. A solution of phenylboronicacid (1.24 g, 10.202 mmol) in 4.5 mL of ethanol was added and themixture was stirred for 10 minutes under the same conditions. A solutionof potassium carbonate (2.16 g, 15.306 mmol) in 3.5 mL of water wasadded to above mixture and the resulting reaction mixture was heated atreflux for 3-4 hours under the argon atmosphere. After the end of thereaction was established by TLC, the reaction was diluted by brine, andextracted with ethyl acetate. The organic layer was washed with brine,dried with MgSO₄, filtered, and concentrated under vacuum. The productwas purified by a silica gel column using ethyl acetate and hexane (1:3to 2:1) as eluent to afford 1.67 g (84.8% yield) of the titled compoundas yellowish oil.

To a solution of 4-phenyl-1H-indole (0.42 g, 0.002173 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.22 g,0.005434 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.76 g, 0.002173 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.69 g(69%) of the titled compound as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H, NH), 8.37 (d, J=2.0 Hz, 1H,ArH), 8.18 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.4 Hz, 1H,ArH), 7.60-7.54 (m, 3H, ArH), 7.49-7.45 (m, 2H, ArH), 7.38-7.34 (m, 2H,ArH), 7.18-7.14 (m, 1H, ArH), 7.04 (d, J=7.2 Hz, 1H, ArH), 6.51 (d,J=3.2 Hz, 1H, ArH), 6.35 (s, 1H, OH), 4.58 (d, J=14.4 Hz, 1H, CH), 4.38(d, J=14.4 Hz, 1H, CH), 1.45 (s, 3H, CH₃).

Mass (ESI, Positive): 464.1536[M+H]⁺; 486.1351[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-5-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(42)

To a solution of 4-fluoro-5-phenyl-1H-indole (0.33 g, 0.00156 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.16g, 0.00391 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.55 g, 0.00156 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.47 g(63%) of the titled compound as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.35 (d, J=2.0 Hz, 1H,ArH), 8.17 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.4 Hz, 1H,ArH), 7.51-7.40 (m, 5H, ArH), 7.36-7.32 (m, 2H, ArH and indole-H),7.17-7.13 (m, 1H, ArH), 6.53 (d, J=3.2 Hz, 1H, ArH), 6.38 (s, 1H, OH),4.60 (d, J=14.8 Hz, 1H, CH), 4.38 (d, J=14.8 Hz, 1H, CH), 1.45 (s, 3H,CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): 482 0.1490 [M+H]⁺; 5040.1310 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-6-(4-fluorophenyl)-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(43)

4-Fluoro-6-(4-fluorophenyl)-1H-indole

To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄,0.27 g, 0.2336 mmol] in 10 mL of ethylene glycol dimethyl ether (DME)was added 6-bromo-4-fluoro-indole (0.50 g, 2.336 mmol), and the mixturewas stirred for 15 minutes under argon at RT. A solution of4-fluoro-phenylboronic acid (0.33 g, 2.336 mmol) in 1.2 mL of ethanolwas added and the mixture was stirred for 10 minutes under the sameconditions. A solution of potassium carbonate (0.48 g, 3.504 mmol) in1.0 mL of water was added to above mixture and the resulting reactionmixture was heated at reflux for 3-4 h under the argon atmosphere. Afterthe end of the reaction was established by TLC, the reaction was dilutedby brine, and extracted with ethyl acetate. The organic layer was washedwith brine, dried with MgSO₄, filtered, and concentrated under vacuum.The product was purified by a silica gel column using ethyl acetate andhexane (1:3) as eluent to afford 0.33 g (61.6% yield) of the titledcompound as brown solid.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-6-(4-fluorophenyl)-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(43)

To a solution of 4-fluoro-6-(4-fluorophenyl)-1H-indole (0.32 g, 0.0014mol) in anhydrous THF (10 mL), which was cooled in an ice water bathunder an argon atmosphere, was added sodium hydride (60% dispersion inoil, 0.17 g, 0.00419 mol). After addition, the resulting mixture wasstirred for three hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.49 g, 0.00140 mol) was added to the above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.35 g(50.5%) of the titled compound as off-white solid.

¹HNMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H, NH), 8.26 (d, J=2.0 Hz, 1H,ArH), 8.07 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 7.97 (d, J=8.8 Hz, 1H,ArH), 7.68-7.64 (m, 2H, ArH), 7.60 (s, 1H, ArH), 7.35 (d, J=3.0 Hz, 1H,ArH), 7.28-7.24 (m, 2H, ArH)), 7.04 (dd, J=12.0 Hz, J=1.2 Hz, 1H, ArH),6.48 (d, J=1.0 Hz, 1H, ArH), 6.39 (s, 1H, OH), 4.67 (d, J=14.8 Hz, 1H,CH), 4.42 (d, J=14.8 Hz, 1H, CH), 1.49 (s, 3H, CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): 499.2056[M+H]⁺.

Synthesis of 3,5-difluoro-1H-indole

To a 50 mL round-bottle flask with a magnetic stirring bar were addedSelectfluor® (872 mg, 2.0 mmol, 2.0 equiv), Li₂CO₃ (296 mg, 4.0 mmol,4.0 equiv), dichloromethane (3.3 mL) and water (1.7 mL). Then5-fluoro-1H-indole-3-carboxylic acid (1.0 mmol, 1.0 equiv) was added.The reaction mixture was stirred for 2 hours in ice bath. The reactionmixture was diluted with water (40 mL), followed by extracting with DCM(20 mL×2). The combined organic extracts were washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (n-hexane:DCM=2:1)to afford 3,5-difluoro-1H-indole as deep brown oil. Yield=68%;

MS (ESI) m/z 154.83[M+H]⁺; 152.03 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 7.86 (bs, 1H, NH), 7.25 (dd, J=9.2, 2.4 Hz,1H), 7.20-7.16 (m, 1H), 6.97 (t, J=2.6 Hz, 1H), 6.93 (dd, J=9.2, 2.4 Hz,1H);

¹⁹F NMR (CDCl₃) δ−123.99 (d, J_(F-F)=2.8 Hz), −174.74 (d, J_(F-F)=4.0Hz).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3,5-difluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(44)

To a dry, nitrogen-purged 50 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (63 mg, 1.56 mmol) was added in 10 mL of anhydrous THF solvent inthe flask at ice-water bath, and 3,5-difluoro-1H-indole (120 mg, 0.78mmol) was stirred 30 min at the ice-water bath. Into the flask,(R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(275 mg, 0.78 mmol) in 10 mL of anhydrous THF was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H₂O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, evaporated, dried overanhydrous MgSO₄, and evaporated to dryness. The mixture was purifiedwith flash column chromatography as an eluent EtOAc/hexane=1/2 toproduce 44 as white solid as white powder.

Yield 53%;

MS (ESI) m/z 424.11[M+H]⁺; 423.11 [M−H]⁻;

HRMS (ESI) m/z calcd for C₂₀H₁₅F₅N₃O₂ [M+H]⁺; Exact Mass: 424.1084[M+H]⁺. Found: 424.1065 [M+H]⁺;

HPLC: t_(R) 2.77 min, purity 99.06%, UV (λ_(abs)) 196.45, 270.45 nm

¹H NMR (CDCl₃, 400 MHz) δ 8.80 (bs, 1H, NH), 7.89 (d, J=1.6 Hz, 1H),7.77 (dd, J=8.4, 1.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.33-7.29 (m, 1H),7.20 (dd, J=9.0, 2.4 Hz, 1H), 6.99 (t, J=2.8 Hz, 1H), 6.97 (td, J=9.0,2.4 Hz, 1H), 4.56 (d, J=14.8 Hz, 1H), 4.24 (d, J=14.8 Hz, 1H), 2.57 (s,OH), 1.61 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 172.3, 157.5 (d, J_(F-F)=235 Hz), 140.9,135.8, 134.1 (d, J F-F=32.8 Hz), 130.4 (d, J_(F-F)=4.5 Hz), 123.4,121.9, 120.6, 117.4 (q, J_(F-F)=4.9 Hz), 115.3, 113.1 (d, J_(F-F)=2.59Hz), 111.1 (d, J_(F-F)=9.3 Hz), 105.0, 102.3, 102.2, 102.0 (d,J_(F-F)=25 Hz), 77.6, 53.9, 24.2;

¹⁹F NMR (CDCl₃) δ−62.25, −123.48 (d, J_(F-F)=3.2 Hz), −173.54 (d,J_(F-F)=2.8 Hz); assigned by 2D NMR as NOE and COSY.

(S)-3-(3-Chloro-5-fluoro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(45)

To a dry, nitrogen-purged 50 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (167 mg, 2.5 mmol) was added in 10 mL of anhydrous THF solvent inthe flask at ice-water bath, and 3-chloro-5-fluoro-1H-indole (170 mg, 1mmol) was stirred 30 min at the ice-water bath. Into the flask,(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(351 mg, 1 mmol) in 10 mL of anhydrous THF was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H₂O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, evaporated, dried overanhydrous MgSO₄, and evaporated to dryness. The mixture was purifiedwith flash column chromatography as an eluent EtOAc/hexane=1/2 toproduce 45 as white solid as white powder.

Yield 58%;

MS (ESI) m/z 440.08 [M+H]⁺; 439.01 [M−H]⁻;

HRMS (ESI) m/z calcd for C₂₀H₁₅ClF₄N₃O₂ Exact Mass: m/z C₂₀H₁₅ClF₄N₃O₂:440.0789 [M+H]⁺; 440.0797 [M+H]⁺;

HPLC: t_(R) 2.89 min, purity 99.06%;

UV (λ_(abs)) 196.45, 270.45 nm;

¹H NMR (CDCl₃, 400 MHz) δ 8.76 (bs, 1H, NH), 7.86 (s, 1H), 7.78-7.73 (m,2H), 7.34 (dd, J=9.2, 4.0 Hz, 1H), 7.29 (dd, J=8.8, 2.4 Hz, 1H), 7.17(s, 1H), 6.97 (td, J=9.2, 2.4 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 4.28 (d,J=14.8 Hz, 1H), 2.64 (s, OH), 1.61 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 172.3, 157.5 (d, J_(F-F)=235 Hz), 140.8,135.8, 134.0 (d, J_(F-F)=32 Hz), 132.6, 126.9, 126.2 (d, J_(F-F)=10 Hz),123.4, 117.4 (q, J_(F-F)=4.9 Hz), 115.3, 112.0 (d, J_(F-F)=26.4 Hz),111.1 (d, J_(F-F)=9.5 Hz), 106.1, 106.0, 105.0, 103.5 (d, J_(F-F)=25Hz), 77.5, 53.8, 24.2.

¹⁹F NMR (CDCl₃) δ−62.25, −12.76; assigned by 2D NMR as NOE and COSY.

(S)-1-((4-Cyano-3-(trifluoromethyl)phenyl)amino)-3-(5-fluoro-1H-indol-1-yl)-2-methyl-1-oxopropan-2-ylacetate (46)

Under argon atmosphere, to a solution of 11 (100 mg, 0.247 mmol) andtriethyl amine (0.07 mL, 0.5 mmol) in 10 mL of anhydrous DCM was addedacetyl chloride (0.02 mL, 0.3 mmol) at ice-water bath. After stirringfor 30 min, the temperature was raised to room temperature and themixture stirred for 2 hours. The reaction mixture was washed with water,evaporated, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentEtOAc/hexane (1/1, v/v) to produce target product as white solid.

Yield=86%;

MS (ESI) m/z 446.0 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.75 (bs, 1H, C(O)NH), 7.88 (s, 1H, ArH),7.79-7.73 (m, 2H, ArH), 7.35 (dd, J=8.8, 4.2 Hz, 1H, ArH), 7.22 (dd,J=9.6, 2.6 Hz, 1H, ArH), 7.16 (d, J=2.6 Hz, 1H, ArH), 6.94 (m, 1H, ArH),6.46 (d, J=3.2 Hz, 1H, ArH), 4.65 (d, J=14.8 Hz, 1H, CH₂), 4.33 (d,J=14.8 Hz, 1H, CH₂), 2.59 (s, 3H, OC(O)CH₃), 1.57 (s, 3H, CH₃);

¹⁹F NMR (CDCl₃, 400 MHz) δ−62.24, −124.54; assigned by 2D NMR as NOE andCOSY.

Carbazole Methods A and B: Preparation of Carbazoles

Method A (non microwave): A mixture of phenyl trifluoromethanesulfonate(500 mg, 2.21 mmol), palladium acetate (II) (50 mg, 0.22 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (317 mg, 0.66 mmol) andcesium carbonate (1.09 g, 3.31 mmol) in 50 mL of toluene were inertizedwith argon. Then, substituted aniline (2.43 mmol) was added and themixture was heated at 110° C. overnight. The reaction mixture wasallowed to cool to RT and filtered through a pad of Celite®. Thefiltrate was diluted with CH₂Cl₂ and water. The phases were separatedand the aqueous phase was re-extracted 2 times with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄ and the solvent was evaporated.

Method B (microwave): A mixture of phenyl trifluoromethanesulfonate (200mg, 0.88 mmol), palladium acetate (II) (20 mg, 0.09 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (64 mg, 0.13 mmol) andcesium carbonate (430 mg, 1.32 mmol), and substituted aniline (0.97mmol) in 5 mL of toluene were loaded into a vessel with a cap. Reactionvessels were placed in a reactor block in the microwave. A programmablemicrowave irradiation cycle of 30 min at 300 W at 110° C. and 25 min offan-cooling was executed (irradiation time, 30 min). The mixture wastransferred to a round bottom flask to be concentrated under reducedpressure and poured into EtOAc, which was washed with water and driedover anhydrous MgSO₄, concentrated. The crude product obtained waspurified by chromatography on silica gel using EtOAc/hexane (6/1, v/v)as an eluent to produce the target product (˜89%) as deep brown oil.

4-Fluoro-N-phenyl aniline: ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.24 (m, 2H),7.07-7.02 (m, 2H), 7.01-6.95 (m, 4H), 6.89 (t, J=7.2 Hz, 1H), 5.57 (bs,1H, NH).

3-Nitro-9H-carbazole

A mixture of phenyl trifluoromethanesulfonate (500 mg, 2.21 mmol),palladium acetate (II) (50 mg, 0.22 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (317 mg, 0.66 mmol) andcesium carbonate (1.09 g, 3.31 mmol) in 50 mL of toluene were inertizedwith argon. Then, 4-nitroaniline (331 mg, 2.43 mmol) was added and themixture was heated at 110° C. overnight. The reaction mixture wasallowed to cool to RT and filtered through a pad of Celite®. Thefiltrate was diluted with CH₂Cl₂ and water. The phases were separatedand the aqueous phase was re-extracted 2 times with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄ and the resulting solution wasdried over anhydrous Na₂SO₄ and purified with flash columnchromatography as an eluent EtOAc/hexane (1/6, v/v) to give4-nitro-N-phenylaniline. The aniline (450 mg, 2 mmol), Pd(OAc)₂ (23 mg,0.1 mmol), K₂CO₃ (30 mg, 0.2 mmol), and pivalic acid (408 mg, 4 mmol)was placed into a glass test tube. The uncapped test tube was placed inan oil bath and the mixture was stirred under air at the indicatedtemperature. The solution was then cooled to RT, diluted with EtOAc,washed with a saturated Na₂CO₃, dried over Na₂SO₄, concentrated, andpurified by flash column chromatography as an eluent of EtOAc/hexane togive 3-nitro-9H-carbazole.

(S)-3-(9H-Carbazol-9-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(200)

Method B: Yield 88%; MS (ESI) m/z 436.1 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.82 (bs, 1H, NH), 8.09-8.06 (m, 3H), 7.84 (d,J=1.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.45-7.39 (m,3H), 7.24-7.23 (m, 2H), 4.80 (d, J=15.2 Hz, 1H), 4.63 (d, J=15.2 Hz, 1H)2.57 (s, 1H, OH), 1.69 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-nitro-9H-carbazol-9-yl)propanamide(201)

Method B: MS (ESI) m/z 481.1 [M−H]⁻

¹H NMR (CDCl₃, 400 MHz) δ 9.01 (s, 1H), 8.92 (bs, 1H, NH), 8.39 (m, 1H),8.08 (m, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.62 (dd,J=8.4, 1.6 Hz, 1H), 7.45 (m, 1H), 7.48-7.22 (m, 3H), 4.91 (d, J=15.0 Hz,1H), 4.85 (d, J=15.0 Hz, 1H) 2.62 (s, 1H, OH), 1.70 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(202)

To a solution of 4-fluoro-carbazole (0.20 g, 0.00108 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.09 g,0.00216 mol). After addition, the resulting mixture was stirred for twohours.(R)-3-Bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide(0.38 g, 0.00108 mol) was added to the above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using methylenechloride as eluent to afford 0.36 g (73.5%) of the titled compound aswhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ10.36 (s, 1H, NH), 8.25 (d, J=1.6 Hz, 1H,ArH), 8.12-8.09 (m, 2H, ArH), 8.04 (d, J=8.8 Hz, 1H, ArH), 7.95 (dd,J=9.2 Hz, J=2.1 Hz, 1H, ArH), 7.66 (t, J=4.8 Hz, 1H, ArH), 7.64 (s, 1H,ArH), 7.37 (dt, J=9.2 Hz, J=1.2 Hz, 1H, ArH), 7.20 (td, J=9.2 Hz, J=2.0Hz, 1H, ArH), 7.13 (t, J=8.0 Hz, 1H, ArH), 6.34 (s, 1H, OH), 4.70 (d,J=14.8 Hz, 1H, CH), 4.55 (d, J=14.8 Hz, 1H, CH), 1.52 (s, 3H, CH₃).

Mass (ESI, Negative): 453.9 [M−H]⁻; (ESI, Positive): 478.1 [M+Na]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(3-fluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(203)

To a solution of 3-fluoro-carbazole (0.10 g, 0.00054 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.033 g,0.00081 mol). After addition, the resulting mixture was stirred for twohours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.17 g, 0.00054 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using hexane andethyl acetate (2:1) as eluent to afford 0.22 g (98%) of the titledcompound as white solid/needles.

¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H, NH), 8.12 (d, J=7.6 Hz, 1H,ArH), 8.05 (d, J=2.0 Hz, 1H, ArH), 7.96 (dd, J=9.2 Hz, J=2.0 Hz, 1H,ArH), 7.86 (d, J=8.8 Hz, 1H, ArH), 7.80 (dd, J=8.4 Hz, J=2.0 Hz, 1H,ArH), 7.69-7.66 (m, 2H, ArH), 7.41 (t, J=8.0 Hz, 1H, ArH), 7.24 (dt,J=9.6 Hz, J=2.4 Hz, 1H, ArH), 7.16 (t, J=7.2 Hz, 1H, ArH), 6.34 (s, 1H,OH), 4.70 (d, J=15.2 Hz, 1H, CH), 4.54 (d, J=15.2 Hz, 1H, CH), 1.52 (s,3H, CH₃).

Mass (ESI, Negative): 420.1[M−H]⁻; (ESI, Positive): 444.1[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(204)

To a solution of 3,6-difluorocarbazole (0.20 g, 0.00098 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.06g, 0.001476 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.266 g, 0.00098 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexane (1:2) as eluent to afford 0.40 gof the titled compound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.22 (d, J=1.6 Hz, 1H,ArH), 8.11 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.8 Hz, 1H,ArH), 7.98 (d, J=2.4 Hz, 1H, ArH), 7.96 (d, J=2.4 Hz, 1H, ArH),7.68-7.65 (m, 2H, ArH), 7.27-7.22 (m, 2H, ArH), 6.36 (s, 1H, OH), 4.72(d, J=15.2 Hz, 1H, CH), 4.54 (d, J=15.2 Hz, 1H, CH), 1.53 (s, 3H, CH₃).

Mass (ESI, Negative): 471.9[M−H]⁻; (ESI, Positive): 496.1[M+Na]⁺.

(S)-3-(9H-Carbazol-9-yl)-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(205)

Method B

Yield 77%;

MS (ESI) m/z 402.3 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 8.75 (bs, 1H, NH), 8.08 (d, J=7.6 Hz, 2H),7.78 (d, J=1.6 Hz, 1H), 7.56-7.54 (m, 3H), 7.44 (t, J=7.6 Hz, 2H), 7.37(dd, J=8.8, 1.8 Hz, 1H), 7.27-7.25 (m, 2H), 4.78 (d, J=15.6 Hz, 1H),4.63 (d, J=15.6 Hz, 1H), 2.65 (bs, 1H, OH), 1.66 (s, 3H).

Isoquinoline Derivative

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-3,4-dihydroisoquinolin-2(11-1)-yl)-2-hydroxy-2-methylpropanamide(132)

Method A

Yield 69%;

MS (ESI) m/z 420.0 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs, 1H, NH), 7.93 (d, J=8.4 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.86 (m, 1H), 6.63 (d,J=8.0 Hz, 1H), 3.71 (s, 2H), 3.42 (d, J=13.2 Hz, 1H), 2.91-2.82 (m, 5H),2.60 (d, J=13.2 Hz, 1H), 1.46 (s, 3H).

Indoline Derivatives

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(103)

Preparation of LDA solution in THF: To a stirred solution of freshlydistilled diisopropylamine (0.14 mL, 1.2 mmol) in anhydrous 5 mL of THFwas added a solution of n-butyllithium (0.53 mL, 1.32 mmol, 2.5 Msolution in hexane) at −78° C. under argon atmosphere. Under the argonatmosphere into a 100 mL dried two necked round bottom flask equippedwith a dropping funnel, the prepared solution of LDA or commercial 2.0 MLDA solution (1.2 mmol, Aldrich) in THF was placed in the flask, andthen 4-fluoroindoline (1.0 mmol) in 10 mL of anhydrous THF was dropwiseadded to the LDA solution at the −78° C. under argon atmosphere. Thesolution was stirred for 10 min and warmed to 0° C. and cooled downagain to −78° C. To the solution, a solution of(R)-3-bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(1.0 mmol in THF) was added through dropping funnel under argonatmosphere at −78° C. and allowed to warm gradually to RT and stirredovernight. And then quenched by an addition of 0.5 mL of sat. NH₄C₁. Thesolution was reduced in volume under reduced pressure and dispersed intoexcess EtOAc, and then dried over anhydrous MgSO₄. The solution wasconcentrated on and purified by flash column chromatography(EtOAc/hexane) or recrystallized from EtOAc/hexane (or DCM/hexane) togive the designed compound, 103.

Yield 71%.

White solid.

MS (ESI) m/z 372.0 [M−H]⁻.

HRMS (ESI) m/z calcd for C₁₉H₁₈ClFN₃O₂: 374.1072. Found: 374.1072[M+H]⁺.

[α]_(D) ²⁰−173° (c 1.0, CH₃OH).

¹H NMR (acetone-d₆, 400 MHz) δ 9.84 (bs, 1H, NH), 8.26 (d, J=2.0 Hz,1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.99 (m, 1H),6.43 (d, J=8.0 Hz, 1H), 6.31 (t, J=8.4 Hz, 1H), 5.21 (bs, 1H, OH), 3.66(m, 1H), 3.63 (d, J=14.4 Hz, 1H), 3.53 (q, J=8.0 Hz, 1H), 3.26 (d,J=14.4 Hz, 1H), 2.89 (m, 2H), 1.53 (s, 3H).

¹³C NMR (acetone-d₆, 100 MHz) δ 175.9, 160.6 (d, J=239.7 Hz), 160.6 (d,J=9.3 Hz), 144.6, 137.3, 135.6, 129.9 (d, J=8.7 Hz), 120.8, 119.2,116.7, 114.8 (d, J=21.7 Hz), 107.8, 105.1 (d, J=21.0 Hz), 104.1 (d,J=8.0 Hz), 77.8, 60.4, 56.7, 25.4, 24.3.

¹⁹F NMR (CDCl₃, decoupled) δ 118.95.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(104)

Method A

Yield; 68%.

¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs, 1H, NH), 7.98 (d, J=2.0 Hz, 1H),7.61 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (m, 1H), 6.77(m, 1H), 6.51 (m, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.56 (bs, 1H, OH), 3.42(m, 1H), 3.30 (q, J=9.2 Hz, 1H), 3.21 (d, J=14.4 Hz, 1H), 3.01 (t, J=8.4Hz, 2H), 1.54 (s, 3H).

MS (ESI) m/z 372.0 [M−H]⁻;

[α]_(D) ²⁰−202° (c 1.0, CH₃OH)

¹⁹F NMR (CDCl₃, decoupled) δ 125.35.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(6-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(106)

Method A

Yield 76%.

MS (ESI) m/z 372.1 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.08 (bs, 1H, NH), 7.97 (d, J=1.6 Hz, 1H),7.60 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 6.77 (t, J=6.4 Hz,1H), 6.39 (m, 1H), 6.33 (d, J=10.0 Hz, 1H), 3.64 (d, J=14.2 Hz, 1H),3.49 (bs, 1H, OH), 3.47 (m, 1H), 3.38 (q, J=9.2 Hz, 1H), 3.23 (d, J=14.2Hz, 1H), 2.95 (m, 2H), 1.56 (s, 3H).

(S)-3-(5-Chloro-6-fluoroindolin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(107)

Method A

Yield; 47%.

MS (ESI) m/z 440.3 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.15 (bs, 1H, NH), 8.08 (s, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.42 (d,J=10.0 Hz, 1H), 3.66 (d, J=14.4 Hz, 1H), 3.52-3.42 (m, 2H), 3.38 (s, 1H,OH), 3.21 (d, J=14.4 Hz, 1H), 2.96-2.80 (m, 2H), 1.52 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5,6-difluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(108)

Method A

Yield; 59%.

MS (ESI) m/z 423.9 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.18 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H),7.97 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.89 (t, J=8.8 Hz,1H), 6.43 (m, 1H), 3.64 (d, J=14.4 Hz, 1H), 3.46 (s, 1H, OH), 3.40-3.35(m, 2H), 3.17 (d, J=14.4 Hz, 1H), 2.99-2.91 (m, 2H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(indolin-1-yl)-2-methylpropanamide(109)

Method A

Yield 69%.

MS (ESI) m/z 387.8 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.24 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H),7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.13-7.10 (m, 2H),6.78 (dt, J=8.0, 0.8 Hz, 1H), 6.62 (d, J=8.0, 1H), 3.77 (bs, 1H, OH),3.66 (d, J=14.4 Hz, 1H), 3.54 (t, J=8.4 Hz, 1H), 3.46-3.40 (m, 1H), 3.30(d, J=14.4 Hz, 1H), 3.04-2.92 (m, 2H), 1.57 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5,6-difluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(110)

Method A

Yield 64%.

MS (ESI) m/z 390.0 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.05 (bs, 1H, NH), 7.98 (s, 1H), 7.62 (d,J=8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 6.88 (t, J=8.8 Hz, 1H), 6.43 (m,1H), 3.64 (d, J=14.4 Hz, 1H), 3.46 (s, 1H, OH), 3.44 (m, 1H), 3.42-3.34(m, 1H), 3.16 (d, J=14.4 Hz, 1H), 3.95-3.88 (m, 2H), 1.55 (s, 3H).

(S)-3-(5-Bromoindolin-1-yl)-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(114)

Method A

Yield 54%.

MS (ESI) m/z 433.6 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.04 (bs, 1H, NH), 7.98 (d, J=2.0 Hz, 1H),7.60 (d, J=6.0 Hz, 1H), 7.52 (dd, J=6.0, 2.0 Hz, 1H), 7.19-7.17 (m, 2H),6.49 (d, J=8.4 Hz, 1H), 3.65 (d, J=14.4, 1H), 3.47 (bs, 1H, OH),3.36-3.41 (m, 1H), 3.32 (q, J=9.2 Hz, 1H), 3.23 (d, J=14.4, 1H),2.99-2.91 (m, 2H), 1.56 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-6-phenylindolin-1-yl)-2-hydroxy-2-methylpropanamide(115)

To a solution of(S)—N-(3-chloro-4-cyanophenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(34, 0.185 g, 0.000413 mol) in 5 mL of glacial acetic acid, which wascooled in an ice-water bath, was added drop-wise sodium cyanoborohydride(1.0 M in THF, 0.62 mL, 0.00124 mol) under as argon atmosphere. Afteraddition, the resulting reaction mixture was allowed to stir forovernight at RT under argon. The reaction was quenched by aqueous NH₄C₁solution, and extracted with ethyl acetate. The organic layer was washedwith brine twice, dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using ethylacetate and hexane (1:2) as eluent to afford 0.17 g of the titledcompound as yellowish foam.

¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H, NH), 8.21 (d, J=2.0 Hz, 1H,ArH), 7.92-7.84 (m, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 6.95 (d, J=10.4Hz, 1H, ArH), 6.55 (d, J=6.4 Hz, 1H, ArH), 6.02 (s, 1H, OH), 3.61 (q,J=8.8 Hz, 1H, CH), 4.50 (d, J=14.4 Hz, 1H, CH), 3.40 (d, J=14.4 Hz, 1H,CH), 4.19 (d, J=14.4 Hz, 1H, CH), 2.91 (t, J=8.4 Hz, 2H, CH₂), 1.42 (s,3H, CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): 450.1394[M+H]⁺.

Indazole Derivatives

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(90) and(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indazol-2-yl)-2-hydroxy-2-methylpropanamide(91)

Method B

Yield; 67%.

MS (ESI) 405.1 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 9.16 (bs, 1H, NH), 8.05-7.88 (m, 2H),7.81-7.72 (m, 2H), 7.62-7.13 (m, 4H), 6.72 (bs, OH, 0.56H), 6.15 (s, OH,0.44H), 4.94 (d, J=13.6 Hz, 0.56H), 4.95 (d, J=14.2 Hz, 0.46H), 4.52 (d,J=13.6 Hz, 0.56H), 4.43 (d, J=14.2 Hz, 0.46H), 1.53 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(92) and(S)—N-(3-chloro-4-cyanophenyl)-3-(5-fluoro-1H-indazol-2-yl)-2-hydroxy-2-methylpropanamide(93)

Method B

Yield; 74%.

MS (ESI) 370.8 [M−H]⁻.

¹H NMR (400 MHz, CDCl₃) δ 8.97 (bs, 1H, NH), 7.99 (s, 0.56H), 7.95 (s,0.46H), 7.83 (d, J=2.4 Hz, 0.46H), 7.83 (d, J=2.0 Hz, 0.54H), 7.64-7.45(m, 2H), 7.39-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.16-7.11 (m, 1H), 6.63(s, OH, 0.46H), 6.04 (s, OH, 0.54H), 4.92 (d, J=13.6 Hz, 0.46H), 4.92(d, J=14.0 Hz, 0.54H), 4.50 (d, J=13.6 Hz, 0.46H), 4.40 (d, J=14.0 Hz,0.54H), 1.58 (s, 3H).

Synthesis of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(94) and(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-2H-indazol-2-yl)-2-hydroxy-2-methylpropanamide(95)

To a dry, nitrogen-purged 50 mL round-bottom flask, R-bromo amide of 8R(351 mg, 1 mmol), 4-fluoro-1H-indazole (136 mg, 1 mmol) and K₂CO₃ (415mg, 3 mmol) were dissolved into 10 mL of DMF. The mixture was heated upto 80° C. and stirred overnight at that temperature. The resultingmixture was cooled down to RT. The volume of mixture was reduced underreduced pressure and poured into water, and extracted with ethyl acetate(3 times). The organic layer was dried over MgSO₄, concentrated andpurified by flash column chromatography (ethyl acetate/hexane 1:2 v/v)on silica gel to produce two products (total 65% yield; 94 (36% yield atR_(f)=0.14) and 95 (29% yield at R_(f)=0.12).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(94)

HRMS (ESI) m/z calcd for C₁₉H₁₅F₄N₄O₂: 407.1131 [M+H]⁺. Found: 407.1150[M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 9.10 (bs, 1H, NH), 8.11 (d, J=0.8 Hz, 1H),7.91 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (d, J=8.4 Hz,1H), 7.41-7.36 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.80 (dd, J=9.6, 7.2 Hz,1H), 6.02 (s, 1H, OH), 4.93 (d, J=14.0 Hz, 1H), 4.43 (d, J=14.0 Hz, 1H),1.53 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−62.25, −117.48.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-2H-indazol-2-yl)-2-hydroxy-2-methylpropanamide(95)

HRMS (ESI) m/z calcd for C₁₉H₁₅F₄N₄O₂: 407.1131 [M+H]⁺. Found: 407.1168[M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 9.15 (bs, 1H, NH), 8.08 (s, 1H), 7.96 (d,J=1.6 Hz, 1H), 7.84 (dd, J=8.8, 1.6 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H),7.42 (d, J=8.8 Hz, 1H), 7.26 (m, 1H), 6.72 (dd, J=10.0, 7.2 Hz, 1H),6.67 (bs, 1H, OH), 4.96 (d, J=13.6 Hz, 1H), 4.54 (d, J=13.6 Hz, 1H),1.54 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−62.41, −116.55.

2-Dimensional nuclear Overhauser effect (NOE) spectroscopy (NOESY):NOESY was used to assign the correct chemical structures to these twoisomers. 94 demonstrated NOEs between the aromatic proton located at the7-position of the indazole ring (annotated as H) and the methyleneprotons (annotated as H₁ and H₂),

indicating that the point of attachment to the indazole ring must be the1-position. Whereas for 95, an NOE was observed between 3-positionaromatic proton of the indazole ring (annotated as H) and the methyleneprotons (annotated as H₁ and H₂),

indicating that the point of attachment to the indazole ring must be the2-position.

Synthesis of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-indazol-1-yl)propanamide(96) and(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-2H-indazol-2-yl)propanamide(97)

To a dry, nitrogen-purged 100 mL round-bottom flask equipped a droppingfunnel under argon atmosphere, NaH of 60% dispersion in mineral oil (160mg, 4.0 mmol) was added in 30 mL of anhydrous THF solvent to the flaskat ice-water bath, and then 4-trifluoromethyl-indazole (b) (372 mg, 2.0mmol) was stirred in over 30 min at the ice-water bath. Into the flask,a prepared solution of epoxide (a), (541 mg, 2.0 mmol) in 10 mL ofanhydrous THF was added through dropping funnel under argon atmosphereat the ice-water bath and stirred overnight at RT. After adding 1 mL ofH₂O, the reaction mixture was condensed under reduced pressure, and thendispersed into 50 mL of EtOAc, washed with 50 mL (×2) water, evaporated,dried over anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography as an eluent EtOAc/hexane at a1:2 ratio to produce compounds 97 (22.9%, @ rf=0.29) and 96 (30.1%, @rf=0.37) as white solids (total 53% yield).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-indazol-1-yl)propanamide(96)

HRMS (ESI) m/z calcd for C₂₀H₁₄F₆N₄O₂ Exact Mass: 457.1099 [M+H]⁺.Found: 457.1117 [M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.08 (bs, 1H, NH), 8.19 (t, J=1.2 Hz, 1H),7.90 (d, J=1.6 Hz, 1H), 7.61-7.70 (m, 3H), 7.55-7.47 (m, 2H), 5.93 (bs,1H, OH), 5.01 (d, J=14.0 Hz, 1H), 4.47 (d, J=14.0 Hz, 1H), 1.55 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−61.54, 62.27.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-2H-indazol-2-yl)propanamide(97)

HRMS (ESI) m/z calcd for C₂₀H₁₄F₆N₄O₂ Exact Mass: 457.1099 [M+H]⁺.Found: 457.1110 [M+H]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.09 (bs, 1H, NH), 8.14 (s, 1H), 7.92 (d,J=2.0 Hz, 1H), 7.85-7.82 (m, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.44 (dt,J=6.8, 0.8 Hz, 1H), 7.41 (q, J=8.4 Hz, 1H), 6.56 (bs, 1H, OH), 4.98 (d,J=14.0 Hz, 1H), 4.57 (d, J=14.0 Hz, 1H), 1.54 (s, 3H).

¹⁹F NMR (CDCl₃, 400 MHz) δ−61.28, 62.55.

2-Dimensional nuclear Overhauser effect (NOE) spectroscopy (NOESY):NOESY was used to assign the correct chemical structures to these twoisomers. 96 demonstrated an NOE between the aromatic proton located atthe 7-position of the indazole ring (annotated as H₂) and the methyleneprotons (each annotated as H),

indicating that the point of attachment to the indazole ring must be the1-position. Whereas for 97, an NOE was observed between 3-positionaromatic proton of the indazole ring (annotated as H₁) and the methyleneprotons (each annotated as H),

indicating that the point of attachment to the indazole ring must be the2-position.

3,5-Difluoro-1H-indazole

To a 50 mL round-bottle flask with a magnetic stirring bar were addedSelectfluor® (872 mg, 2.0 mmol, 2.0 equiv), Li₂CO₃ (296 mg, 4.0 mmol,4.0 equiv), dichloromethane (3.3 mL) and water (1.7 mL). Then5-fluoro-1H-indazole-3-carboxylic acid (1.0 mmol, 1.0 equiv) was added.The reaction mixture was stirred for 2 hours in ice bath. The reactionmixture was diluted with water (40 mL), followed by extracting with DCM(20 mL×2). The combined organic extracts were washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (n-hexane:DCM=2:1)to afford the desired product.

Yield 48%;

MS (ESI) m/z 152.0 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 9.80 (bs, 1H, NH), 7.37 (dt, J=8.8, 2.4 Hz,1H), 7.31 (dd, J=8.0, 1.6 Hz, 1H), 7.23 (td, J=8.8, 2.0 Hz, 1H);

¹⁹F NMR (CDCl₃) δ−121.46 (d, J_(F-F)=4.4 Hz), −133.92 (d, J_(F-F)=4.4Hz).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3,5-difluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(98)

To a dry, nitrogen-purged 50 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (32 mg, 0.8 mmol) was added in 5 mL of anhydrous THF solvent in theflask at ice-water bath, and 3,5-difluoro-1H-indazole (60 mg, 0.41 mmol)was stirred 30 min at the ice-water bath. Into the flask,(R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(148 mg, 0.41 mmol) in 5 mL of anhydrous THF was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H2O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, evaporated, dried overanhydrous MgSO₄, and evaporated to dryness. The mixture was purifiedwith flash column chromatography as an eluent EtOAc/hexane=2/3 toproduce 98 as white solid.

Yield=57%;

MS (ESI) m/z 423.17 [M−H]⁻; 447.21 [M+Na]⁺;

¹H NMR (CDCl₃, 400 MHz) δ 9.07 (bs, 1H, NH), 7.92 (s, 1H), 7.78 (d,J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.28 (m,1H), 7.25 (m, 1H), 5.28 (bs, 1H, OH), 4.82 (d, J=14.0 Hz, 1H), 4.27 (d,J=14.0 Hz, 1H), 1.52 (s, 3H);

¹⁹F NMR (CDCl₃, 400 MHz) δ−61.27, −120.39, −131.15; assigned by 2D NMRas NOE and COSY.

Example 5

Androgen Receptor Binding, Transactivation, and Metabolism of Indole,Benzimidazole, and Indazole SARDs

Ligand Binding Assay

Objective: To determine SARD binding affinity to the AR-LBD.

Method: hAR-LBD (633-919) was cloned into pGex4t.1. Large scaleGST-tagged AR-LBD was prepared and purified using a GST column.Recombinant AR-LBD was combined with [³H]mibolerone (PerkinElmer,Waltham, Mass.) in buffer A (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA,0.25 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determine theequilibrium dissociation constant (K_(d)) of [³H]mibolerone. Protein wasincubated with increasing concentrations of [³H]mibolerone with andwithout a high concentration of unlabeled mibolerone at 4° C. for 18 hin order to determine total and non-specific binding. Non-specificbinding was then subtracted from total binding to determine specificbinding and non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻² M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BioGel® HT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

Transactivation Assay for wt and Mutant AR

Objective: To determine the effect of SARDs on androgen-inducedtransactivation of AR wildtype (wt) or AR carrying known AR-LBD mutants(i.e., W741L or T877A).

Method: HEK-293 cells were plated at 125,000 cells/well of a 24 wellplate in DME+5% csFBS without phenol red. Cells were transfected with0.25 ug GRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) orCMV-hAR(W741L) or CMV-hAR(T877A) using lipofectamine transfectionreagent in optiMEM medium. Medium was changed 24 h after transfection toDME+5% csFBS without phenol red and treated with a dose response ofvarious drugs (Table 1: 11-18, 20-27, 30, 31, 33, 70-74) (1 pM to 10μM). SARDs and antagonists were treated in combination with knownagonist 0.1 nM R1881 in order to produce an antagonism curve. Luciferaseassay was performed 24 h after treatment on a Biotek synergy 4 platereader. Firefly luciferase values were normalized to renilla luciferasevalues. For FIG. 1A-1C, the following variation of the method was used:

HEK cells were plated in 24 well plates at 60,000 cells per well inDMEM+5% csFBS without phenol red. After overnight incubation, changedmedium to OptiMEM (0.25 ml). All the wells were transfected with 0.25 ugGRE-LUC, 5 ng CMV-renilla LUC, and 25 ng CMV-hAR. Twenty four hoursafter transfection, medium was replaced with 1 ml of DME+5% csFBSwithout phenol red. Twenty-four hrs after transfection, the cells weretreated with 20, 18, and 14 (FIG. 1A), 12 and 11 (FIG. 1B), 11, 27, and23 (FIG. 1C), or 34-42 (FIGS. 29A, 29B, 29D-29I, 29K, & 29O) and wereharvested 48 hrs after transfection and firefly and renilla luciferaseassay performed.

Transactivation. HEK-293 cells were plated at 120,000 cells per well ofa 24 well plate in DME+5% csFBS. The cells were transfected usingLipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC, 0.01μg CMV-LUC (renilla luciferase) and 25 ng of the AR, PR, GR, or MR. Thecells were treated 24 hrs after transfection as indicated in the figuresand the luciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ values obtained from four parameter logistics curve.

AR Degradation Using Compounds of this Invention

Objective: To determine the efficacy and potency of AR degradation bySARD compounds in AD1 cells (full-length), LNCaP (T877A AR), D567es(splice variant lacking exons 5,6,&7) or 22RV-1 (full length AR andtruncated splice variant AR (AR-V7)) cell lines.

Method: See Example 6 below.

Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds: Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/NIS analysis: The analysis of the compounds under investigationwas performed using LC-MS/MS system consisting of Agilent 1100 HPLC withan MDS/Sciex 4000 Q-Trap™ mass spectrometer. The separation was achievedusing a C₁₈ analytical column (Alltima^(rm), 2.1×100 mm, 3 μm) protectedby a C₁₈ guard cartridge system (SecurityGuard™ ULTRA Cartridges UHPLCfor 4.6 mm ID columns, Phenomenex). Mobile phase was consisting ofchannel A (95% acetonitrile+5% water+0.1% formic acid) and channel C(95% water+5% acetonitrile+0.1% formic acid) and was delivered at a flowrate of 0.4 mL/min. The volume ratio of acetonitrile and water wasoptimized for each of the analytes. Multiple reaction monitoring (MRM)scans were made with curtain gas, collision gas, nebulizer gas, andauxiliary gas optimized for each compound, and source temperature at550° C. Molecular ions were formed using an ion spray voltage (IS) of−4200 V (negative mode). Declustering potential, entrance potential,collision energy, product ion mass, and cell exit potential wereoptimized for each compound.

Log P: Octanol-Water Partition Coefficient (Log P)

Log P is the log of the octanol-water partition coefficient, commonlyused early in drug discovery efforts as a rough estimate of whether aparticular molecule is likely to cross biological membranes. Log P wascalculated using ChemDraw Ultra version is 12.0.2.1016 (Perkin-Elmer,Waltham, Mass. 02451). Calculated Log P values are reported in Tables 3& 6 in the column labeled Log P (−0.4 to +5.6). Lipinski's rule of fiveis a set of criteria intended to predict oral bioavailability. One ofthese criteria for oral bioavailability is that the Log P is between thevalues shown in the column heading (−0.4 (relatively hydrophilic) to+5.6 (relatively lipophilic) range), or more generally stated <5. One ofthe goals of SARD design was to improve water solubility.

TABLE 1 AR Binding, Inhibition of AR (wt and Mutant) Transactivation, ARDegradation and in vitro Metabolic Stability of Indole and BenzimidazoleSARDs. Transcriptional Activation (+0.1 nM R1881; R1881 EC₅₀ = 0.11 nM)SARD activity T_(1/2) (min) Binding Wt W741L T877A (FIG. numbersCL_(int) Compound K_(i) (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) herein)(μl/min/mg) DHT 1 — — — R-Bicalutamide 545.5 248.2 — 557 Enzalutamide205.2 216.3 939 331.94 3, 9C ARN-509 — 297.0 1939.41 390.50 3, 5, 6B, 14(apalutamide) ASC-J9 — 1008.0 3487.68 2288.16 5, 6A 11 57.8 33.4-27213.68 48.47 2A, 3, 5, 6C, 9C 12.35 min 56.14 μl/min/mg 11R — 351.21 — —12 314.22 103.34 3, 11, 14 37.27 18.6 13 625.01 —  3 14 223.74 71.8115.97 (partial) 43.4 15 >10,000 — 29.79 23.28 16 489.88 2285.14 17 80.4318 416.03 322.99 21.07 32.9 20 432.69 88.03 2A, 3, 4, 11, 12 19.27 35.9721 293.84 984.52 20.37 34.02 22 419.35 126.73 36.32 19.08 23 212.4985.10 11 22.39 30.96 24 315.84 917.68 12 17.02 40.73 27 2079.94 63.69 1113.66 50.75 30 995.23 971.78 (11 12 25.78 38 nM in the 26.89 same exp)31 547.27 157.41 13, 15 21.77 31.84 33 >10,000 684.64 70 530.72 299.7816 72 — 1016 32 46.58 57.76 11 13.48 51.43 73 724.07 998.56 16 741399.69 720.61

The short half-lives (t_(1/2)) and high metabolic clearance (CL_(int))values in vitro of many of the compounds of this invention suggest rapidplasma clearance which could be favorable for topical treatment ofandrogenic dermatologic disorders as it would limit the risk of systemicside effects, even if the skin is penetrated.

AR transactivation assay was performed with wildtype, W741L, and T877AAR constructs. W741 mutation to leucine or cysteine (L/C) confersresistance to bicalutamide (Hara, T., Miyazaki, J., Araki, H., Yamaoka,M., Kanzaki, N., Kusaka, M., and Miyamoto, M. (2003). Novel mutations ofandrogen receptor: a possible mechanism of bicalutamide withdrawalsyndrome. Cancer Research 63, 149-153), while T877 mutation results inresistance to hydroxyflutamide (Tan, J., Sharief, Y., Hamil, K. G.,Gregory, C. W., Zang, D. Y., Sar, M., Gumerlock, P. H., deVere White, R.W., Pretlow, T. G., Harris, S. E., et al. (1997). Dehydroepiandrosteroneactivates mutant androgen receptors expressed in the androgen-dependenthuman prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol11, 450-459). 11 potently inhibited the R1881-induced wildtype ARtransactivation with much higher potency than enzalutamide (FIG. 37A).While 11 effectively antagonized both wildtype and mutant ARscomparably, similar to enzalutamide, was weaker in W741L mutant AR (FIG.37B). Although 11 inhibited glucocorticoid receptor (GR) andmineralocorticoid receptor (MR) transactivation only at ˜10 μM, itcross-reacted with the progesterone receptor (PR) robustly (FIG. 37C).

Kennedy's disease is a neuromuscular disease caused by AR with anextended polyglutamine tract (La Spada, A. R., Wilson, E. M., Lubahn, D.B., Harding, A. E., and Fischbeck, K. H. (1991). Androgen receptor genemutations in X-linked spinal and bulbar muscular atrophy. Nature 352,77-79). While in normal healthy humans, the AR contains 15-24polyglutamines, in patients suffering from Kennedy's disease, thepolyglutamine tracts are extended to over 40 or even 100 repeats (LaSpada et al., 1991). This extended polyglutamine tract results in ARmis-folding causing neuromuscular toxicity (La Spada et al., 1991).

11 was tested in a transactivation assay with the AR containing anextended polyglutamine tract. 11 inhibited the R1881-stimulatedtransactivation of the AR that contains 65 polyglutamine repeats (FIG.37D) with an IC₅₀ value comparable to that observed with the wildtypeAR.

AR N—C interaction is a measure of the AR activity (He et al., 2002) andinhibiting the AR N—C interaction is another measure of antagonisticactivity. A mammalian two hybrid assay was performed with aGal-4-DBD-fused AR-LBD, VP16 activation domain fused AR-NTD, and a doseresponse of 11. 11 inhibited the R1881-induced AR N—C interaction atconcentrations comparable to that observed in AR transactivation (FIG.37E).

TABLE 2 Binding Affinity of Indole SARDs of this Invention. Relativebinding Compound K_(i) (nM) affinity (RBA) DHT 8.88 1.00 6.62 12 817.30.011 11 57.8 0.152  11R 333.07 0.027 14 179.77 0.049 15 663.05 0.010

FIGS. 1A-1C and FIGS. 29A-29O and Tables 1-3 show that many of the SARDsof this invention had higher AR binding affinity (see tables) and morepotent AR antagonism in vitro (see Tables 1˜4 and figures referencedabove and in the tables) than all the other AR antagonists tested(bicalutamide, enzalutamide, ARN-509, and ASC-J9). Further compounds 11(Table 1 above) and 96 (Table 10 of Example 10) retained highly potentantagonist activity in the two resistance mutants tested unlike theknown antiandrogens tested.

TABLE 3 AR Binding (K_(i)), Inhibition of AR Transactivation (IC₅₀), ARDegradation and Metabolic Stability of Indole Based SARDs. SARD ActivityDMPK Binding/ Full S.V. (MLM) Transactivation (wt AR) Length (22RV1)T_(1/2) (min) LogP K_(i) (nM) % % CL_(int) ( −0.4 (DHT = IC₅₀ inhibitioninhibition (μl/min/ Compd ID Structure to +5.6 ) 1 nM (nM) at 1,10 μM at10 μM mg) Enobosarm

3.44      20.21     ~20 R- Bicalutamide

2.57     508.84      248.2 Enzalutamide

4.56     3641.29      216.3 ARN-509 (apalutamide)

3.47     1452.29  0  0

2.57      87.67 —

1.86     407.08 27

3.31     2079.94      63.69  13, 89 13.66 50.75 22

3.47     419.35     126.73  54, 81 36.32 19.08 11

3.47     267.39      85.10  65-83  60-100 12.35 56.14 11R

3.47  >10000     589.84  83 23

3.47     212.49      85.10  0, 100 22.39 30.96 12

3.34     314.22     103.34  43, 100 37.27 18.6 20

3.34     432.69      88.03  45, 100  78 19.27 35.97 32

3.34     46.58      57.76  0, 100 13.48 51.43 24

4.14     315.84     917.68  0 17.02 40.73 21

4.67     293.84     984.52  13 20.37 34.02 18

4.23     416.03     335.98  74, 79  47 21.07 32.9 16

3.18     489.88     2285.14 13

3.80     625.01 —  52, 86 17

3.87      80.43     545.48  0, 0 14

3.34     223.74      71.81 (partial antagonism)     1018.73 (agonist(EC₅₀)) 15.97 43.4 15

2.87 >10,000 — 29.79 23.28 19

5.33 —

6.09 — 30

3.47     995.23     971.78 (11 was 38 nM in the same exp) 25.78 26.89 31

3.95     547.27     157.41 21.77 31.84 70, 71 (mixture)

2.70     530.72     299.78  50 48.58 14.27 72

4.56 —     1016 73

2.86     724.07     998.56  7, 68 74

3.50     1399.69     720.61  51  0 75

2.70   >1000     973.15  14 (Figure 33B) 76

2.70     1588.62     1023.94 (Figure 33A) 77

3.47      492.56 >10,000  50 78

3.47      474.38     3616  76 79

2.34      882.75     1661.97 80

2.85 >10,000     684.64 33

5.14     124.66     214.66  54  22 15.43 44.94 34

4.78     132.94 See Figure 29O     202.67 See Figure 29O  55 (Figure29O)  41 (Figure 29O)  9.131 75.91 35

3.10      155.74 See Figure 29K      98.47  65, 80 (Figure 29K)  0 36

3.10     315.32 See Figure 291     141.99 See Figure 291  71 (Figure291)  41 11.77 58.8 37

3.10     252.58 See Figure 29H      94.33 See Figure 29H  81 (Figure29H)  30 (Figure 29H) 38

3.10     331.79 (Figure 29G)      44.50 (Figure 29G)  68 (100 nM)(Figure 29G)  62 (Figure 29G)  9.291 74.6 39

3.10     719.81 (Figure 29F)     233.8 (Figure 29F)  40 (Figure 29F)  4590, 91 (mixture)

3.08, 3.45     806.67     851.94  0  8 92, 93 (mixture)

2.72, 3.08 No binding (Figure 29E)     946.84 (Figure 29E)  40 (Figure29E)  80 (Figure 29E) 94

3.08     137.47     172.86  92  34 13.29 52.16 95

3.45     171.84 No effect  0  0 96

3.84     1006.38     372.87  70 (Figure 33C) 53.71 12.91 97

4.21     1232.45     208.78 (Figure 33D) 35.46 19.55 98

3.71     182.1 40

4.78     134.88 See Figure 29D     1032.14 See Figure 29D  0  0 41

4.98      84.32 See Figure 29B  >10000 See Figure 269  0  0 42

5.14      86.18 See Figure 29A     1015.12 See Figure 29A  0  0 43

5.3      62.34      897.5 100 44

3.63     317.64      274.3  72  84 45

4.03     754.7      366.9  60  80 46

3.7     134.19      133.1  90 100

TABLE 3A AR Binding (K_(i)), Inhibition of AR Transactivation (IC₅₀), ARDegradation and in vitro Metabolic Stability of SARDs. SARD ActivityDMPK Full S.V. (MLM) Binding/ Length (22RV1) T_(1/2) (min) LogPTransactivation (wt AR) % % CL_(int) (−0.4 K_(i) (nM) inhibitioninhibition (μl/min/ Compd ID Structure to +5.6) (DHT = 1 nM IC₅₀ (nM) at1, 10 μM at 10 μM mg) Enobosarm

3.44 20.21   ~20 R- Bicalutamide

2.57 508.84    248.2 Enzalutamide

4.56 3641.29    216.3 ARN-509

3.47 1452.29  0 0

2.57 87.67 —

1.86 407.08 300

4.25 No effect 301

3.87 — 302

3.87 — 301/302

3.87 No effect 303

3.48 3615    277 70 0 304

3.11    687 60 0 305

3.11 1476    560 40 0 306

3.78   2594 nM    308

4.79 No effect

TABLE 4 Liver Microsome (LM) Data of Indole and Benzimidazole SARDs inMouse LM (MLM), Human LM (HLM), Rat LM (RLM) and Dog LM (DLM). MLM HLMRLM DLM Compd T_(1/2) CL_(int) T_(1/2) CL_(int) T_(1/2) CL_(int) T_(1/2)CL_(int) ID (min) (μl/min/mg) (min) (μl/min/mg) (min) (μl/min/mg) (min)(μl/min/mg) 27 13.66 50.75 22 36.32 19.08 (4-F) 11 14.35 48.30 14.6247.40 (5-F) 23 22.39 30.96 (6-F) 12 37.27 18.60 (4-NO₂) 20 19.27 35.9717.97 38.57 (5-NO₂) 32 13.48 51.43 (6-NO₂) 24 17.02 40.73 (5-Br) 2129.39 20.37 (5-1) 18 37.71 18.38 (5-CF₃) 14 15.97 43.40 (5-CN) 15 29.7823.28 (3-CO₂H) 30 25.78 26.89 13.77 0.05034 70, 71 48.58 14.27 16.3642.37 31 21.77 31.84[ 33 15.43 44.94 7.31 94.82 34 9.131 75.91 15.5058.87 38 9.291 74.6 6.611 104.9 36 11.77 58.8 12.66 54.7

Example 6

Androgen Receptor Binding and Transactivation, AR Degradation, and invitro Metabolism of Indoline, Quinolone and Isoquinoline based SARDs(Tables 5-7)

Ligand Binding Assay

Objective: To determine SARDs binding affinity to the AR-LBD.

Method: hAR-LBD (633-919) was cloned into pGex4t.1. Large scaleGST-tagged AR-LBD was prepared and purified using a GST column.Recombinant ARLBD was combined with [³H]mibolerone (PerkinElmer,Waltham, Mass.) in buffer A (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA,0.25 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determine theequilibrium dissociation constant (K_(d)) of [³H]mibolerone. Protein wasincubated with increasing concentrations of [³H]mibolerone with andwithout a high concentration of unlabeled mibolerone at 4° C. for 18 hin order to determine total and non-specific binding. Non-specificbinding was then subtracted from total binding to determine specificbinding and non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻²M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using Bio Gel HT® hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

Transactivation Assay with Wt AR

Objective: To determine the effect of SARDs on androgen-inducedtransactivation of AR wildtype (wt).

Method: HEK-293 cells were plated at 125,000 cells/well of a 24 wellplate in DME+5% csFBS without phenol red. Cells were transfected with0.25 ug GRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) usingLipofectamine transfection reagent in optiMEM medium. Medium was changed24 h after transfection to DME+5% csFBS without phenol red and treatedwith a dose response of various drugs (1 pM to 10 μM). SARDs andantagonists were treated in combination with 0.1 nM R1881. Luciferaseassay was performed 24 h after treatment on a Biotek synergy 4 platereader. Firefly luciferase values were normalized to renilla luciferasevalues. (Tables 5 and 6)

Plasmid Constructs and Transient Transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ obtained from four parameter logistics curve.

LNCaP Gene Expression Assay.

Method: LNCaP cells were plated at 15,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Forty-eight hours after plating,cells were treated with a dose response of SARDs. Twenty four hoursafter treatment, RNA was isolated using cells-to-ct reagent, cDNAsynthesized, and expression of various genes was measured by realtimertPCR (ABI 7900) using taqman primers and probes. Gene expressionresults were normalized to GAPDH.

LNCaP Growth Assay.

Method: LNCaP cells were plated at 10,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method: LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 μM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method: 22RV1 and D567es cells expressing AR splice variants were platedat 750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 Growth and Gene Expression.

Methods: Cell growth was evaluated as described before by SRB assay.Cells were plated in a 96 well plate in full serum and treated for 6days with medium change after day 3. Gene expression studies wereperformed in 22RV1 cells plated in 96 well plate at 10,000 cells/well inRPMI+10% FBS. Twenty four hours after plating, cells were treated for 3days and gene expression studies were performed as described before.

Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds (Table 7) Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage of −4200 V (negative mode).Declustering potential, entrance potential, collision energy, production mass, and cell exit potential were optimized for each compound.

TABLE 5 AR Binding (K_(i)), Inhibition of AR Transactivation (IC₅₀), ARDegradation and in vitro Metabolic Stability of Indoline, Quinoline andIsoquinoline SARDs. SARD activity DMPK (estimated (MLM)Binding/Tranactivation (wtAR) median effect T_(1/2) (min) Compd IDStructure K_(i) (nM) IC₅₀ (nM) (nM)) CL_(int) (μl/min/mg) Enobosarm

  8.385 ~20 R-Bicalutamide

 211.12 248.2 — Enzalutamide

678.9 216.3 — ARN-509 (apalutamide)

>1000    + (FIG. 18) 100

 23.17  34.16 530.95 10-100 (FIGS. 18 & 19) 66.87 min 10.38 μl/min/mg101

 83.1 58.96 100-500 (FIG. 25) 25.06 min 27.67 μl/min/mg 102

126.8 26.28 100-500 (FIGS. 19 & 21) 55.14 min 12.57 μl/min/mg 103

 382.44 126.13 10000 (FIG. 22) 104

 326.14 130.37 10-100 (FIG. 22) 29.16 min 23.77 μl/min/mg 105

 273.04 38.74 (FIG. 25) 106

 489.95 36.45 (FIG. 25) 130

1530.58 420.07 1000-5000 (FIGS. 19, 20, 23 & 24) 161.7 min 4.286μl/min/mg 134

 201.98 573.98 5000-10000 (FIG. 24) 38.25 min 18.12 μl/min/mg 135

3112.73 867.48 10-100 nM (FIG. 21) 15.25 min 45.45 μl/min/mg 131

 398.63 1002.73 — 25.42 min 27.27 μl/min/mg 107

 67.65 74.65 (FIG. 25) 67 108

 114.84 100.55 (FIG. 25) 81

The short half-lives (t_(1/2)) and high metabolic clearance (CL_(int))values in vitro of some of the compounds of this invention suggest rapidplasma clearance for those compounds which could be favorable fortopical treatment of androgenic dermatologic disorders as it would limitthe risk of systemic side effects, even if the skin is penetrated. Othercompounds demonstrate relatively long half-lives and low metabolicclearances values in vitro suggesting that these compounds may be ableto achieve systemic exposures necessary to have systemic antiandrogeneffects such as would be necessary to treat prostate cancer.

TABLE 6 AR Binding (K_(i)), Inhibition of AR Transactivation (IC₅₀), ARDegradation and Metabolic Stability of Indoline, Quinoline andIsoquinoline SARDs. SARD Activity DMPK Binding/Transactivation S.V.(MLM) Log P (wt AR) Full Length (22RV1) T_(1/2) (min) (−0.4 to K_(i)(nM) % inhibition % inhibition CL_(int) (μl/ Compd ID Structure +5.6)(DHT = 1 nM IC₅₀ (nM) at 1.10 μM at 10 μM min/mg) Enobosarm

3.44  20.21 ~20  R-Bicalutamide

2.57 508.84 248.2 Enzalutamide

4.56 3641.29 216.3 ARN-509 (apalutamide)

3.47 1452.29 0    0 DJ-I-223

2.57  87.67 — DJ-VI-5E

1.86  407.08 100

4.62  197.67  530.95 60   41 66.87 10.38 101

3.95  169.86  58.96 61    5 25.06 27.67 102

3.95  807.22  137.04 95   63 55.14 12.57 103

3.59  382.44  126.13 58   71 15   46.22 104

3.59  326.14  130.37 47.69 15 29.16 23.77 105

3.95  273.04  38.74 60   30 106

3.59  489.95  36.45 99   12 107

4.51  67.65 Agonist 30-48  0 108

4.11  114.84  100.55 54   36 109

3.80 >1000     142.13 84   45 110

3.75  251.94  31.71 79   40 114

4.25  204.36 See FIG. 26M  834.68 See FIG. 26M 37.84 (FIG. 29M)  0 (FIG.29M) 17.35 39.36 115

5.27  71.48 See FIG. 26J  244.43 See FIG. 26J 93 (100 nM) (FIG. 29J) 90(FIG. 29J) 21.37 32.44 130

4.28 1530.58  420.07 70.78 65 161.7   4.286 131

3.61  398.63 1002.73 24 25.42 27.27 132

3.61  353.19 (FIG. 29C legend)  978.91 (FIG. 29C) 0   60 134

5.04  201.98  573.98 38.25 18.12 135

4.37 3112.37  867.48 21 15.25 45.45

TABLE 7 Liver Microsome (LM) Data for Indoline, Quinoline andIsoquinoline SARDs in Mouse LM (MLM), Human LM (HLM), Rat LM (RLM), andDog LM (DLM). MLM HLM RLM DLM Compd T_(1/2) CL_(int) T_(1/2) CL_(int)T_(1/2) CL_(int) T_(1/2) CL_(int) ID (min) (μl/min/mg) (min) (μl/min/mg)(min) (μl/min/mg) (min) (μl/min/mg) 102 55.14 0.01257 (5F- indoline) 10066.87 10.38 64.84 0.01069 (5Br- indoline) 102 28.13 24.64 17.71 39.13101 25.06 27.67 135 15.21 45.57 7.54 91.94 131 25.42 27.27 6.553 105.8104 29.16 23.77 24.7 28.06 3.33 208 49.44 14 103 15 46.22 20.07 34.542.09 330 42.8 16.19 114 17.35 39.96 6.084 113.9 115 21.37 32.44 11.7758.87

Example 7

AR Degradation Using Compounds of this Invention (Indoles,Benzimidazoles, Indazoles)

LNCaP Gene Expression Assay

Objective: To determine the effect of SARDs on AR-target gene expressionin LNCaP cells.

Method: LNCaP cells were plated at 15,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Forty-eight hours after plating,cells were treated with a dose response of SARDs. Sixteen-twenty fourhours after treatment, RNA was isolated using cells-to-ct reagent, cDNAsynthesized, and expression of various genes was measured by realtimertPCR (ABI 7900) using taqman primers and probes. Gene expressionresults were normalized to GAPDH.

LNCaP Growth Assay

Objective: To determine the effect of SARDs on LNCaP cell growth.

Method: LNCaP cells were plated at 10,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP Degradation Assay

Objective: To determine the effect of SARDs on AR expression in LNCaPcells.

Method: LNCaP cells were plated at 750,000-1,000,000 cells/well of a 6well plate in growth medium (RPMI+10% FBS). Twenty four hours afterplating, medium was changed to RPMI+1% csFBS without phenol red andmaintained in this medium for 2 days. Medium was again changed toRPMI+1% csFBS without phenol red and cells were treated with SARDs (1 nMto 10 μM) in combination with 0.1 nM R1881. After 16-20 h of treatment,cells were washed with cold PBS and harvested. Protein was extractedusing salt-containing lysis buffer with three free-thaw cycles. Proteinconcentration was estimated and five microgram of total protein wasloaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane.The membrane was probed with AR N-20 antibody from SantaCruz and actinantibody from Sigma.

22RV-1 Degradation Assay

Objective: To determine the effect of SARDs on AR full length and splicevariant expression in 22RV-1 cells.

Method: 22RV-1 cells were plated at 750,000-1,000,000 cells/well of a 6well plate in growth medium (RPMI+10% FBS). Twenty four hours afterplating, medium was changed and treated. After 16-20 h of treatment,cells were washed with cold PBS and harvested. Protein was extractedusing salt-containing lysis buffer with three free-thaw cycles. Proteinconcentration was estimated and five microgram of total protein wasloaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane.The membrane was probed with AR N-20 antibody from SantaCruz and actinantibody from Sigma.

AD1 Androgen Receptor Degradation (Full Length AR)

Objective: To determine the effect of compounds of this invention(SARDs) on full length AR protein expression in AD1 cells.

Method: AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, the medium was changedto RPMI+1% csFBS without phenol red and maintained in this medium for 2days. The medium again was changed to RPMI+1% csFBS without phenol redand cells were treated with SARDs (1 nM to 10 mM) in combination with0.1 nM R1881. After 24 h of treatment, cells were washed with cold PBSand harvested. Protein was extracted using salt-containing lysis bufferwith three freeze-thaw cycles. The protein concentration was estimatedand five microgram of total protein was loaded on a SDS-PAGE,fractionated, and transferred to a PVDF membrane. The membrane wasprobed with AR N-20 antibody (SantaCruz Biotechnology, Inc., Dallas,Tex. 75220) and actin antibody (Sigma-Aldrich, St. Louis, Mo.). Theresults of this assay in AD1 cells were reported in FIGS. 33A (76), 33B(75), 33C (96) and 33D (97) as images of Western blot films(chemiluminescence exposed films). Also reported in FIGS. 33A-33D areresults from wt AR binding (K_(i)), inhibition of transactivation(IC₅₀), and in vitro metabolic stability in mouse liver microsomes(MLM). One advantage of the indazole template is metabolic stability invitro compared to indole and benzimidazole analogs. For example, 96(4-CF₃ indazole) demonstrated a half-life of 53.7 minutes and intrinsicclearance of 12.91 μg/min/mg which is a two-fold improvement compared to18 (5-CF₃ indole; 21 min and 32.9 μg/min/mg).

FIG. 2A presents degradation in LNCaP cells using 11 and 20. LNCaP cellswere plated in 6 well plates at 1 million cells/well. The cells weremaintained in serum free condition for 3 days. The cells were treated asindicated in the figure, harvested, protein extracted, and Westernblotted for AR. 11 demonstrated selective degradation of AR (i.e., SARDactivity) in the nM range, i.e., at concentrations comparable to itsantagonist IC₅₀ value. LNCaP cells are known to express the AR mutantT877A, demonstrating the ability to degrade resistance conferring mutantandrogen receptors.

FIG. 2B presents the effect of AR antagonists and SARDs on LNCaP cellgrowth: LNCaP cells were plated in 96 well plates at 10,000 cells/wellin RPMI+1% csFBS without phenol red. Cells were treated as indicated inthe figure in combination with 0.1 nM R1881 for 6 days with mediumchange on day 3. At the end of 6 days, the cells were fixed and stainedwith sulphorhodamine blue stain. 11 demonstrated more potentanti-proliferative activity in LNCaP cells at 1 and 10 μM when comparedto enzalutamide and ARN-509.

FIG. 3 presents AR-V7 degradation (PC3-AR-V7 cells) using 11, 12 and 20at 1 μM and 10 μM. PC-3 prostate cancer cells were serum stablytransfected with a lentivirus construct for AR-V7. Once the stable cellswere selected, the cells were plated in 6 well plates at 1 millioncells/well. The cells were treated as indicated in the figure andWestern blot performed for AR and actin. The results show that the SARDshave the potential to degrade the truncated version of AR, whileenzalutamide or ARN-509 had no effect of the AR-V7 expression.

SARD Compounds of this Invention Degrade AR-SV in 22RV-1 Cells

FIGS. 4-22RV-1 Western blot: 22RV-1 cells were plated in 6 well plate at1-1.5 million cells/well in growth medium (RPMI+10% FBS). Next day,medium was changed and treated with vehicle or a dose response of 20.After overnight treatment (12-16 hrs), cells were washed in ice cold PBSand harvested by scrapping in 1 mL PBS. Cells were pelleted, proteinextracted, quantified using BCA assay, and equal quantity of protein wasfractionated on a SDS-PAGE. The proteins were transferred to nylonmembrane and Western blotted with AR antibody (N20 from SCBT) and actinantibody. 20 was capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-SV) in 22RV-1 cells, suggesting that SARDsmay be able to overcome AR-V7 dependent prostate cancers (e.g., CRPC).11 degraded AR-FL but not actin in LNCaP cells (FIG. 5 ) and AR-FL andAR-SV in 22RV-1 cells (FIGS. 6A-6C). FIGS. 6A-6C show that 11 degradedAR-FL and AR-V7 at nM concentrations (FIG. 6C) whereas ARN-509 did notdegrade either (FIG. 6B). Although ASC-J9 did exhibit some degradationin the nM range, μM concentrations failed to degrade AR (FIG. 6A). 11also inhibited AR-dependent gene expression (PSA and TMPRSS2) in LNCaPcells, transactivation of AR in 22RV-1 cells and cellular growth in boththe cell types (Table 8 and Table 9). Cumulatively, these observationssuggest that SARDs of this invention may be useful in prostate cancersthat are dependent on mutant ARs, AR-FL and/or AR-SV.

FIG. 11 presents degradation in LNCaP cells using 27, 20, 12, 23 and 32.LNCaP cells were plated in 6 well plates at 1 million cells/well. Thecells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. All SARDs demonstrated selective degradationof AR (i.e., SARD activity) at concentrations comparable to theirantagonist IC₅₀ values. LNCaP cells are known to express the AR mutantT877A, demonstrating the ability to degrade antiandrogen resistanceconferring mutant androgen receptors (i.e., advanced prostate cancersand CRPC).

FIG. 12 : 22RV-1 Western blot: 22RV-1 cells were plated in 6 well platesat 1-1.5 million cells/well in growth medium (RPMI+10% FBS). Next day,medium was changed and treated with vehicle or a dose response of 20, 24and 30. After overnight treatment (12-16 hrs), cells were washed in icecold PBS and harvested by scrapping in 1 mL PBS. Cells were pelleted,protein extracted, quantified using BCA assay, and equal quantity wasfractionated on a SDS-PAGE. The proteins were transferred to nylonmembrane and Western blotted with AR antibody (N20 from SCBT) and actinantibody. 20, 24 and 30 were capable of degrading full length androgenreceptor (AR-FL) and truncated AR (AR-V7) in 22RV-1 cells, suggestingthat SARDs may be able to overcome AR-V7 dependent prostate cancers(i.e., CRPC).

FIG. 13 presents degradation in LNCaP cells and 22RV-1 cells using 31vs. galeterone. The experiments were performed by the methods citedabove. A dose response of SARD 31 demonstrated the ability to degradefull length AR in LNCaP and 22RV-1 cell lines, whereas galeterone wasnot able to substantially degrade AR in either cell line.

FIG. 14 presents degradation in LNCaP cells using 12 vs. ARN-509. 12 andARN-509 both demonstrated the ability to degrade AR in LNCaP cells,however 12 demonstrated activity at 1 μM whereas ARN-509 onlydemonstrated activity at 10 μM.

FIG. 15 presents degradation in 22RV-1 cells using 31. Using the methodsdescribed in the legend for FIG. 12 (22RV-1), SARD activity for 31 wasdemonstrated as degradation of full length (AR) and truncated splicevariant (AR-V7) androgen receptor.

FIG. 16 presents degradation in LNCaP cells using benzimidazoles 70 and73. Using the methods described in the legend for FIG. 11 (LNCaP), SARDactivity for 70 and 73 was demonstrated at concentrations as low as 100nM. This demonstrates that benzimidazoles of this invention alsodemonstrate potent SARD activity.

These selected SARD activity demonstrations as well of those reported inthe tables suggest the compounds of this invention are able to degrade avariety of AR variants, and hence should provide the ability to inhibitthe AR-axis activity whether it is androgen-dependent orandrogen-independent. Degradation of the AR removes the possibility ofpromiscuous activation of mutant ARs, activation by intracellularprocesses such as signal transduction, kinase activation, and/or highlevels of coactivators, etc.; and suggests that the SARDs should alsodegrade the polyQ polymorphisms in hyperandrogenic dermatologicdisorders (shortened polyQ) or Kennedy's disease (extended polyQ),providing a rationale for treating either type of disease by destroyingthe AR in the affected tissues (skin and neuromuscular system,respectively).

TABLE 8 Inhibition of Growth and Gene Expression of LNCaP PCa Cells.Gene Expression IC₅₀ (nM) Growth Compound PSA TMPRSS2 IC₅₀ (nM)Bicalutamide 783.7 831.4 Enzalutamide 384.4 72.3 872 Compound 11 5.013.1 271 ARN-509 169.7 517.1 994 ASC-J9 >10,000 >10,000 1064

TABLE 9 Effects of SARDs on AR Transactivation and Growth of 22RV-1Cells Transactivation Growth Compound IC₅₀ (nM) IC₅₀ (nM) Bicalutamide3133.52 >10,000 Enzalutamide 101.87 >10,000 Compound 11 420.62 1041ARN-509 64.54 >10,000 ASC-J9 1026.91 >10,000

To validate the results obtained in 22RV1 cells, AR degradation effectof 11 was tested in various PCa cell lines. AD-1 cells that express onlyAR-FL, D567es cells that express only AR-v567es, and LNCaP-95 cells thatco-express AR-FL and AR-SV (FIG. 38A) were treated under variousconditions with a dose response of 11. Cells were harvested 24 hrs aftertreatment and Western blot for the AR and its isoforms was performed. Asindicated in the figures, 11 consistently degraded the AR and its SVs atconcentrations ranging between 100 and 1000 nM, indicating that theseSARDs degrade the AR and its SVs under various conditions andirrespective of the specific combination of the AR-FL and SV expressed.The D567es result was unexpected based on our hypothesis of SARD bindingsolely to the LBD, and earlier findings [Watson, P. A., Chen, Y. F.,Balbas, M. D., Wongvipat, J., Socci, N. D., Viale, A., Kim, K., andSawyers, C. L. (2010) Constitutively active androgen receptor splicevariants expressed in castration-resistant prostate cancer requirefull-length androgen receptor. Proceedings of the National Academy ofSciences of the United States of America 107, 16759-16765) that theAR-SV function depends on the AR. The D567es result argues for thedirect interaction of the SARDS of this invention with AR-SV such asD567es which lacks themLBD.

To determine if the degradation is a direct effect due todestabilization of already synthesized AR protein, LNCaP and 22RV1 cellswere treated with 11, protein synthesis inhibitor cycloheximide, or acombination of cycloheximide and 11. While 11 degraded the AR and AR-V7starting from 4-6 hrs, addition of cycloheximide accelerated thedegradation, indicating that the 11-dependent AR and AR-SV degradationwas not dependent on the expression of other proteins and that 11destabilized the already synthesized AR and AR-SV (FIG. 38B) at theprotein level. The graph below FIG. 38B shows the reduction in half-lifeof both the AR and AR-SV by 11.

Degradation of the AR and AR-V7 by 11 was rapid and sustained. Toevaluate the time-course of degradation, LNCaP cells were treated with11 in combination with 0.1 nM R1881. Cells were harvested at differenttime-points and Western blot for AR and actin was performed. 11 degradedthe AR starting at 4 hrs with complete degradation observed by 12 hrs(FIG. 39A). Almost comparable time-course was followed for theinhibition of AR function as measured by the expression of the AR-targetgenes PSA and FKBP5 (FIG. 39B). To determine the endurance of thisdegradation upon removal of 11, D567es cells were treated with vehicleor 11 for 24 hrs. Cells were washed and one set of plates was harvestedimmediately (time point 0 hrs), while the rest of the plates wereharvested 24 or 72 hrs after the drug removal. Western blot for AR-V7and actin was performed. AR was degraded by 11 by 24 hrs (time-point 0hrs) and remained degraded up to 72 hrs after the 11 removal (FIG. 39C).

11 degraded the AR through ubiquitin-proteasome degradation machinery.To evaluate the role of ubiquitin-proteasome machinery in theSARD-dependent AR degradation, LNCaP cells were treated with 11 for 4hrs, AR was immunoprecipitated, and a Western blot for ubiquitin wasperformed (FIG. 38C). AR co-immunoprecipitated with ubiquitin in thepresence of 11, indicating that ubiquitination of the AR in response tothese SARDs is a potential mechanism for AR degradation.

11 inhibited AR-dependent gene expression and PCa cell proliferation. Toevaluate whether the highly potent AR antagonism translates toinhibition of AR function and PCa cell proliferation, 11 was tested inLNCaP cells and compared to enzalutamide. Treatment of LNCaP cells with11 inhibited 0.1 nM R1881-induced PSA and FKBP5 gene expression at lownanomolar concentrations with at least 10-fold better potency thanenzalutamide (FIG. 40A).

To determine the effect of 11 on AR-V7-dependent gene expression, PC-3cells stably transfected with AR-V7 were treated with vehicle or 10 μM11 for 24 hrs and RNA-sequencing was performed. Expression of severalgenes was altered by AR-V7, which were reversed back to PC-3-GFP celllevels by 11 (FIG. 40B left panel; selected genes from the list shown inFIG. 40B right panel). These results show that the genes induced byAR-V7 were inhibited by 11. The effect on AR-V7-dependent geneexpression was confirmed in 22RV1 cells, where androgen-independentexpression of FKBP5 was inhibited by 11, but not by enzalutamide (FIG.40C).

The effect of the SARD compounds of this invention on the proliferationof AR-FL- and AR-SV-expressing cell lines was evaluated. R1881-inducedLNCaP proliferation was completely inhibited by 11 with nanomolar IC₅₀,while enzalutamide inhibited the proliferation at concentrations greaterthan 1 μM (FIG. 40D). 11 also inhibited the proliferation of 22RV1 cellsat concentrations between 1 and 10 μM, while enzalutamide failed toinhibit the proliferation (FIG. 40D). These results were reproduced invarious cell lines, including LNCaP-abl and LNCaP-EnzR, both containingenzalutamide-resistant AR, and in AR-SV-expressing LNCaP-95 cells. 11modestly inhibited the proliferation of HeLa cells at 30 μM,demonstrating its specificity. In addition to these cells, 11 alsoinhibited the proliferation of AD-1 (FIG. 41A) and transactivation ofv567es AR and proliferation of D567es cells that carry AR-v567es (FIG.41B). 11, but not enzalutamide, inhibited the expression of PSA inLNCaP-EnzR, indicating that the F876L mutant that is resistant toenzalutamide is sensitive to 11 (FIG. 40E).

The SARDs compounds of this invention inhibited the AR nucleartranslocation and recruitment to PSA regulatory regions. To determine ifthe SARD compounds inhibit the recruitment of the AR to cis regulatoryelements, LNCaP cells were treated with 11 in the presence of 0.1 nMR1881. Two hours after the treatment, cells were fixed to cross-link theprotein to DNA, AR was immunoprecipitated, and recruitment to the PSAenhancer was quantified by realtime PCR. 11 inhibited the recruitment ofthe AR to PSA enhancer (FIG. 42A). These studies were performed at atime-point when no AR degradation could be detected.

Inhibition of AR DNA binding could be a result of nuclear translocationinhibition. Microscopic evaluation of nuclear translocation shows that11 inhibited the R1881-induced translocation of F876Lenzalutamide-resistant AR (FIG. 42B).

The SARD compounds of this invention did not require binding to the LBDto degrade the AR. As these SARDs bind to two domains and degrade theAR, they serve as a tool to probe into the role of each domain fordegradation and proliferation. Molecular modeling was performed todetermine the amino acids in the AR-LBD with which 11 interacted. 11formed hydrogen bonds with Q711, R752, N705, and L704 (FIG. 42C). Thesesites were mutated and performed a transactivation assay. Mutating theseamino acids individually compromised the ability of R1881 to activatethe AR. While the EC₅₀ of R1881 for the wildtype AR was 0.11 nM, theEC₅₀ for the mutant ARs was 7.48 nM for Q711A, 8.72 nM for L704A, 15.41nM for R752L, and 2037 nM for N705A (FIG. 42C; left panel).

The effect of 11 was determined on the transactivation of wildtype andmutants AR's. In these studies R1881 was used at the respective EC₅₀ foreach mutant. While 11 effectively inhibited the wildtype ARtransactivation at 63 nM, it inhibited the transactivation of the LBDmutants at concentrations greater than 1 μM. 11 failed to inhibit thefunction of N705A mutant AR (FIG. 42C; right panel). These studies showthat mutating the interacting amino acids in the LBD weaken 11's abilityto inhibit ligand-dependent AR transactivation and that 11's binding toLBD is important to antagonize androgen-dependent function of the AR.

To determine if mutating the LBD will also impact 11's degradation role,HeLa cells transfected with wildtype or mutant ARs were treated with 11and AR expression was evaluated by Western blot. These studies wereperformed under the same conditions as indicated for thetransactivation. 11 degraded the wildtype and mutant ARs comparably(FIG. 42D), indicating that binding to LBD can be spared to retain thedegradation activity.

To confirm this observation the R-isomer of 11 was synthesized (11R). 11has a chiral center and the active form is the S-isomer. Hence, anR-isomer is expected to be a weaker LBD binder than the S-isomer. Wetested the effect of 11R on R1881-induced AR transactivation and ARexpression. While the 11R was 10-fold weaker to inhibit the ARtransactivation, no difference was observed between the S- and R-isomersof 11 in their ability to degrade the AR (FIG. 43 ).

To determine if 11's anti-proliferative effect is dependent on itscompetitive binding to the LBD, we performed proliferation assay inLNCaP cells in the presence of increasing concentrations of R1881. Weexpected that increasing concentration of R1881 will displace 11 fromthe ligand binding pocket, resulting in reduced or lack ofanti-proliferative effects. Interestingly, increasing concentrations ofR1881 weakened enzalutamide's effects, but failed to affect 11's effecton proliferation (FIG. 44 ) suggesting that anti-proliferative effectsare not dependent of competitive binding to the LBD.

Collectively these studies provide compelling evidence to show that 11elicits AR degradation and possibly anti-proliferative activity throughits AF-1, while the antagonistic effect of ligand-dependenttransactivation is through the LBD.

11 inhibited PCa xenografts growth. In vitro studies proved that 11 wereextremely potent to inhibit and degrade both AR and AR-S Vs. 11 wastested in vivo in various xenograft models. In addition to LNCaP and22RV1 xenografts, we developed a PDX, Pr-3001, from a CRPC patientspecimen. Pr-3001 is a CRPC that expresses AR-FL and AR-SV and grows incastrated mice.

Pr-3001 is an aggressively growing patient-derived specimen. Typically,it is very hard to grow patient-derived PCa in mice due to their slowgrowing property. Pr-3001 developed tumors robustly and attainedapproximately 1000 mm³ in less than 2 months. Pr-3001 expresses AR-FLand AR-SV and grows in castrated mice. Pr-3001 at 1 mm³ piece wereimplanted on the flanks of mice and its growth was monitored. WhenPr-3001 attained 100-200 mm³, the animals were randomized and treatedwith vehicle or 11. Consistent with the observations made in 22RV1xenograft, 11 inhibited the growth Pr-3001 by over 50% (FIG. 45 ).

Example 8

AR Degradation Using Indoline, Quinoline, or Isoquinoline SARD Compoundsof this Invention

Plasmid Constructs and Transient Transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ obtained from four parameter logistics curve.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using biogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K.

LNCaP Gene Expression Assay.

Method: LNCaP cells were plated at 15,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Forty-eight hours after plating,cells were treated with a dose response of SARDs. Twenty four hoursafter treatment, RNA was isolated using cells-to-ct reagent, cDNAsynthesized, and expression of various genes was measured by realtimertPCR (ABI 7900) using taqman primers and probes. Gene expressionresults were normalized to GAPDH.

LNCaP growth assay.

Method: LNCaP cells were plated at 10,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method: LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 μM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method: 22RV1 and D567es cells expressing AR splice variants were platedat 750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 Growth and Gene Expression.

Methods: Cell growth was evaluated as described before by SRB assay.Cells were plated in 96 well plate in full serum and treated for 6 dayswith medium change after day 3. Gene expression studies were performedin 22RV1 cells plated in 96 well plate at 10,000 cells/well in RPMI+10%FBS. Twenty four hours after plating, cells were treated for 3 days andgene expression studies were performed as described before.

Results:

FIG. 18 presents degradation in LNCaP cells using 100 compared toARN-509. LNCaP cells were plated in 6 well plates at 1 millioncells/well. The cells were maintained in serum free conditions for 3days. The cells were treated as indicated in the figure, harvestedprotein extracted, and Western blotted for AR. 100 demonstratedselective degradation of AR (i.e., SARD activity) in the nM range, i.e.,at concentrations comparable to its antagonist IC₅₀ value whereasARN-509 only demonstrated SARD activity at the highest concentrationtested. LNCaP cells are known to express the AR mutant T877A,demonstrating the ability of compounds of this invention to degradeantiandrogen resistance conferring mutant androgen receptors.

FIG. 19 demonstrates via Western blot that 100, 102, and 130 degradedAR-FL and AR-SV in 22RV-1 cells. 22RV-1 cells were plated in 6 wellplates at 1-1.5 million cells/well in growth medium (RPMI+10% FBS). Nextday, medium was changed and treated with vehicle or a dose response of100, 102, and 130. After overnight treatment (12-16 hrs), cells werewashed in ice cold PBS and harvested by scrapping in 1 mL PBS. Cellswere pelleted, protein extracted, quantified using BCA assay, and equalquantity of protein was fractionated on a SDS-PAGE. The proteins weretransferred to nylon membrane and Western blotted with AR antibody (N20from SCBT) and actin antibody. 100, 102, and 130 were capable ofdegrading full length androgen receptor (AR-FL) and truncated AR (AR-SV)in 22RV-1 cells, suggesting that SARDs may be able to overcome AR-V7dependent prostate cancers.

FIG. 20 presents degradation in 22RV-1 cells using 130 vs. galeterone.Using the methods described in the legend for FIG. 19 (22RV-1), 130 wascompared to galeterone (a clinical lead SARD). 130 demonstrated SARDactivity in 22RV-1 (growth dependent on AR-SV, an AR variant lacking aLBD) cells which was comparable to galeterone.

FIG. 21 presents degradation in LNCaP cells using 135 and 102. Using themethods described in the legend for FIG. 18 , SARD activities for 135and 102 was demonstrated. These compounds partially and fully degradedmutant AR (T877A), suggesting that SARDs such as these may be useful inadvanced prostate cancer and/or CRPC.

FIG. 22 presents degradation in LNCaP cells and 22RV-1 cells using 103and 104. Using the methods described in the legends for FIG. 18 (LNCaP)and FIG. 19 (22RV-1), 103 and 104 demonstrated SARD activity in bothLNCaP (mutant AR harboring T877A mutation) and 22RV-1 (growth dependenton AR-SV lacking a LBD) cells.

FIG. 23 presents degradation in 22RV-1 cells using 130. Using themethods described in the legend for FIG. 19 , compound 130 demonstratedSARD activity at least at the 10 μM concentration.

FIG. 24 presents degradation in 22RV-1 cells using 134 and 130. Usingthe methods described in the legend for FIG. 19 , compounds 134 and 130each demonstrated SARD activity at least at the 10 μM concentration.

FIG. 25 presents degradation in LNCaP cells using −101, 105, 106, 107and 108. LNCaP cells were plated in 6 well plates at 500,000 cells/welland maintained in RPMI+1% csFBS without phenol red for 2 days. Cellswere treated as indicated above in combination with 0.1 nM R1881 for 24hrs. Cells were harvested 24 hrs after treatment, protein extracted,Western blotted with AR antibody (SantaCruz antibody AR N-20) and actinantibody (Sigma). 101, 105, 106, 107 and 108 each demonstrated theability to degrade the AR in the nM range.

FIGS. 49A and 49B present degradation of FL AR and AR SV by selectedSARDs. LNCaP (FIG. 49A) or 22RV1 (FIG. 49B) cells were plated infull-serum containing medium. Medium was changed to 1% charcoal-strippedserum containing medium and maintained in this medium for 2 days. Mediumwas changed again and the cells were treated with 0.1 nM R1881 (agonist)and either vehicle or a titration of SARD as indicated in the figure.Twenty-four hours after treatment, cells were harvested, proteinextracted, and the proteins were blotted with AR-N20 antibody. Blotswere stripped and re-probed with an actin antibody. AR—full lengthandrogen receptor; AR-SV—androgen receptor splice variant. In FIGS. 49Aand 49B, SARD activity was measured by treating cells with 0.1, 1.0 or10 μM concentrations of SARDs in the presence of agonist (0.1 nM R1881).The Western blots were quantified densitometrically and the AR/Actinvalues are represented as fold change or percent change fromvehicle-treated cells.

FIG. 49A showed the degradation of FL AR in LNCaP cells and FIG. 49Bshowed degradation of SV in 22RV1 cells, while actin in each lane servesas an internal standard to correct for variations in protein loadingwhich complicate the visual interpretation of the immunoblots. Thedegradation values reported in Tables 3 and 6 are normalized forvariations in protein loading and are relied upon for relative efficacydeterminations. Concentration-dependent degradation was seen in LNCaPcells for 115 (3′-C₁, 5-F, 6-Ph indoline), 34(3′-Cl, 5-F, 6-Ph indole),101 (3′-CF₃, 4-F indoline), 104 (3′-C₁, 5-F indoline) and 106 (3′-C₁,6-F indoline). From FIG. 49A, it is apparent that >50% of FL AR isalready degraded at 1 μM of these SARDs, i.e. nM range SARD activity. SVAR degradation (the lower molecular weight band in FIG. 49B; upper bandis disregarded in % degradation values) of 34 (3′-Cl, 5-F, 6-Ph indole),102, 115 (3′-Cl, 5-F, 6-Ph indoline), 103 (3′-Cl, 4-F indoline), and 11(3′-CF₃, 5-F indole) was observed to be dose-dependent and generallyabout 10-fold less potent (FIG. 49B) for selected SARDs, which isconsistent with other SARDs. Some compounds degrade FL AR better than SVAR (e.g., 106) or vice versa (e.g., 32) (Tables 3 and 6), whereas theoptimal SARD potently and completely (i.e., ++++) degrades both and hasa high potency antagonism. 115 comes closest to displaying the perfectprofile with complete/strong degradation of FL/SV and antagonismcomparable to enzalutamide, 0.244 μM (115) vs. 0.216 μM (5).

These selected SARD activity demonstrations and well as other reportedin the tables suggest the compounds of this invention are able todegrade a variety of AR variants, and hence should provide the abilityto inhibit the AR-axis activity whether it is androgen-dependent orandrogen-independent. Degradation of the AR removes the possibility ofpromiscuous activation of mutant ARs, activation by intracellularprocesses such as signal transduction, kinase activation, high levels ofcoactivators, etc.; and suggests that the SARDs should also degrade thepolyQ polymorphisms in hyperandrogenic dermatologic disorders (shortenedpolyQ) or Kennedy's disease (extended polyQ), providing a rationale fortreating either type of diseases by destroying the AR in the affectedtissues (skin and neuromuscular system, respectively). Further, aspectrum of in vitro metabolic stabilities were observed suggesting thepossibility of either topical administration (short half-life such thatsystemic exposure are limited) or systemic (e.g., oral; requiresrelatively long half-lives) administration.

Example 9

SARDs Inhibit Ligand Independent AR Transcription

Compound 11 inhibited transactivation in the AR-NTD-DBD-hinge (A/BCD) ARconstruct which lacks the ligand binding domain (FIGS. 7A-7D). (A.) ARA/BCD increased GRE-LUC reporter activity. AR A/BCD construct that lacksthe ligand binding domain (labeled as A/BCD) or empty vector (labeled aspCR3.1) was transfected into HEK-293 cells along with GRE-LUC andCMV-renilla LUC. Forty eight hours after transfection cells wereharvested and luciferase assay performed. As expected, the empty vectordid not produce a strong signal compared to the A/BCD construct. (B.-D.)AR A/BCD activity was inhibited by 11. AR A/BCD construct that lacks theligand binding domain (LBD) was transfected along with GRE-LUC andCMV-LUC. Cells were treated 24 hrs after transfection as indicated inthe figure and luciferase assay performed 48 hrs after transfection. 11(a SARD) inhibited the activity of construct lacking LBD confirming thebinding to an alternate site in addition to the LBD. Non-SARDantagonists ARN-509 and enzalutamide did not inhibit the activity ofthis AR construct lacking the LBD, suggesting that SARDs can inhibitligand independent AR activity via an alternative binding anddegradation domain (BDD) located outside of the LBD. Subsequently,experiments have indicated the NTD as the location of this binding site(see Example 12).

Example 10

Comparison of SARDs and Clinical Candidates in Binding andTransactivation

Plasmid Constructs and Transient Transfection. Human AR cloned into CMVvector backbone was used for the transactivation study. HEK-293 cellswere plated at 120,000 cells per well of a 24 well plate in DME+5%csFBS. The cells were transfected using Lipofectamine (Invitrogen,Carlsbad, Calif.) with 0.25 mg GRE-LUC, 0.02 mg CMV-LUC (renillaluciferase) and 25 ng of the AR. The cells were treated 24 h aftertransfection as indicated in the figures and the luciferase assayperformed 48 h after transfection. Data are represented as IC₅₀ obtainedfrom a four parameter logistics curve.

FIG. 8A presents the data comparing 11, 12, and 14 with galeterone,EPI-001, and enzalutamide, in the transactivation study. In general theSARDs of this invention were equipotent to more potent than enzalutamdewhich was the most potent known AR antagonist tested. EPI-001 did notdemonstrate any inhibition in this assay. FIG. 8B shows the datacomparing 11 with galeterone and enzalutamide in the transactivationstudy. The results show that the SARD compounds of the present inventionwere several-fold more potent than galeterone and enzalutamide ininhibition of DHT activated AR transactivation in vitro.

FIGS. 34-36 present data comparing compound 96 with enzalutamide,galeterone and ARN-509. FIG. 34 presents the effect of known ARantagonists and SARD 96 on FKBP5. FIG. 35 presents the effect of knownAR antagonists and SARD 96 on PSA. FIG. 36 presents the effect of ARantagonists and SARD 96 on SRB-LNCaP cell growth: LNCaP cells wereplated in 96 well plates at 10,000 cells/well in RPMI+1% csFBS withoutphenol red. Cells were treated as indicated in the figure in combinationwith 0.1 nM R1881 for 6 days with medium change on day 3. At the end of6 days, the cells were fixed and stained with sulphorhodamine bluestain. Table 10 summarizes the above and presents it as a panel of invitro characterizations of 96 with regard to AR binding (K_(i)), nuclearhormone receptor transactivation including AR wt and mutant (IC₅₀), andinhibition of LNCaP cell growth and AR-dependent gene expression inLNCaP cells. 96 binds to the LBD of AR with relatively low affinity (˜1μM) but inhibits AR transactivation in wildtype (301 nM) and T877A (343nM) and W741L (14 nM) mutants with greater potency suggesting that ARinhibition may not be mediated by the LBD. 96 demonstrates good nuclearreceptor specificity with no inhibition of transactivation in theglucocorticoid receptor (GR) and mineralocorticoid receptor (MR), andinhibition in the progesterone receptor (PR) that is 3-fold less potentthan inhibition of the AR (wt). The anti-androgenic activity of 96 isalso evidenced in LNCaP cells, a prostate cancer cell line whose growthis dependent on mutant T877A AR. 96 was anti-proliferative (FIG. 36 )and inhibited AR-dependent gene expression of FKBP5 (FIG. 34 ) and PSA(FIG. 35 ) in LNCaP cells demonstrating the potential for the treatmentof prostate cancer with 96 and other SARDs of this invention based ontheir activity in well known models of prostate cancer such as LNCaPcells. This panel suggests that 96 is more potent in AR escape mutantsthan wt AR unlike the known AR antagonists tested, and more nuclearhormone receptor selective than the AR antagonists in use (enzalutamide)or advanced clinical testing (ARN-509 and galeterone).

TABLE 10 AR Binding (K_(i)), Inhibition of AR (wt and mutants), PR, GR,and MR Transactivation (IC₅₀), LNCaP Cell Growth Inhibition and GeneExpresssion of Compound 96 and Known AR Antagonists. LNCaPTransactivation (IC50 nM) Growth Gene Expression Ki (nM) AR T877A W741LPR GR MR nM PSA FKBP5 96 1006.38 301.26 342.67 14.24 1057 >=10 >101015.23 980.74 105.28 Galeterone >1000 243.84 1530.74 636.02 N.I. >10Enzalutamide >1000 183.41 54.91 619.73 196.97 N.I. >10 304.9 220.6938.08 ARN-509 >1000 216.58 292.52 998.83 1195.9 N.I. >10 1907 >=10 >=10

Ligand binding assay. hAR-LBD (633-919) was cloned into pGex4t.1. Largescale GST-tagged AR-LBD was prepared and purified using a GST column.Recombinant AR-LBD was combined with [³H]mibolerone (PerkinElmer,Waltham, Mass.) in buffer A (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA,0.25 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determine theequilibrium dissociation constant (K_(d)) of [³H]mibolerone. Protein wasincubated with increasing concentrations of [³H]mibolerone with andwithout a high concentration of unlabeled mibolerone at 4° C. for 18 hin order to determine total and non-specific binding. Non-specificbinding was then subtracted from total binding to determine specificbinding and non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR-LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BioGel HT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i). Table 11 shows that the SARD compounds of thepresent invention are at least approximately 8-10 folds more tightlybound than galeterone and enzalutamide in AR binding assay studies.

TABLE 11 Binding Assay Results. Compound Binding (K_(i)) nM 11 62.7 1447.9 12 72.9 Galeterone 922.8 Enzalutamide 678.9 EPI-001 Does Not Bind

Example 11

Compound 11 Inhibits Tumor Growth of an Aggressive Prostate CancerExpressing AR Splice Variant

Xenograft experiment. NOD SCID gamma (NSG) mice (n=8-10) were housed asfive animals per cage and were allowed free access to tap water andcommercial rat chow (Harlan Teklad 22/5 rodent diet—8640). Cell linexenografts were performed as previously published (Narayanan et al.,2010; Yepuru et al., 2013). LNCaP tumors were grown in intact mice,while 22RV-1 tumors were grown in castrated mice. Once tumor sizereached 100 mm³, the animals were randomized and treated with vehiclecontrol (polyethylene glycol: DMSO 9:1 ratio) or 11 (50 mg/kg/day s.c.).Tumor volume was calculated using the formula length*width*width*0.5236.At the end of the experiment, animals were sacrificed, tumors werecollected, weighed, and stored for further analysis. Blood wascollected, serum separated, and serum PSA was measured using ELISA.

All experiments were performed thrice and each in vitro experiment wasperformed in triplicate. Statistical analysis was performed usingJMP-Pro software (SAS; Cary, N.C.). Experiments containing only twogroups were analyzed by simple t-test, while experiments containing morethan two groups were analyzed by One Way ANOVA, followed by appropriatepost-hoc test.

22RV-1 xenograft studies with Compound 11: Since 11 degraded both AR-FLand AR-SV in 22RV-1 and LNCaP cells, the molecule was evaluated in22RV-1 (FIGS. 9A-9D) and LNCaP (FIGS. 10A-10C) xenograft studiesdescribed below. FIGS. 9A-9B show that 11 (100 mg/kg bid) inhibitedtumor growth of a prostate cancer that expresses an AR splice variant(AR-V7) and full-length AR (AR-FL). 22RV-1 is a highly aggressive tumormodel that is unresponsive to any currently available treatments. A SARDcompound of the present invention, 11, restricted its growth byapproximately 50%, whereas enzalutamide (Enzal) was ineffective. Noside-effects were observed in the 3-4 weeks study. FIG. 9C demonstratedthat 11 degraded both AR-FL and AR-V7 in the 22RV-1 xenografts whereasenzalutamide (Enzalu) demonstrated no degradation of either AR in thesexenografts. FIG. 9D demonstrated that 11 but not enzalutamide suppressedserum PSA in xenograft bearing animals, demonstrating that 11 suppressedAR gene expression in these tumors. This demonstrated that 11 but notenzalutamide can overcome the antiandrogen resistance present in 22RV-1cells (e.g., AR-V7 dependent growth) by degrading the AR-V7 and AR-FL,resulting in significantly suppressing androgenic tone in these tumors.This provided a proof-of-concept that SARDs such as 11 would be ofclinical benefit to CRPC patients, particularly if systemic exposurescould be improved.

FIGS. 10A-10C show that 11 (100 mg/kg bid) inhibited LNCaP tumorxenograft growth with a % tumor growth inhibition (% TGI) of 65% (FIG.10A) and inhibited tumor weight by about 50% (FIG. 10B). As shown inFIG. 10C, the serum PSA level was inhibited by >75%, indicating theAR-axis was suppressed in the xenograft as expected for a SARD.Cumulatively, these results indicated that SARDs should be effective inAR-driven prostate cancers regardless of whether the prostate cancersare driven by wt or mutant AR-FL and/or AR-SV such as AR-V7 which lackthe LBD. As such SARDs, would be able to treat enzalutamide orabiraterone resistant prostate cancers.

Example 12

SARDs Bind to the AF1 of NTD of AR

Fluorescent Polarization (FP): There are two tryptophan residues and upto 12 tyrosine residues in the AF1 of the AR which is located in theN-terminal domain (NTD) of AR. This has allowed the study of the foldingproperties of this domain using intrinsic steady state fluorescenceemission spectra. Excitation at 287 nm excites both tyrosine andtryptophan residues. The emission maximum (λmax) for the tryptophan issensitive to the exposure to solvent. In the presence of the naturalosmolyte TMAO there is a characteristic ‘blue shift’ consistent with thetryptophan residues being less solvent exposed and a loss of theshoulder (˜307 nm) for tyrosine as there is increased energy transfer totryptophan as the polypeptide folds. To test if the compounds (anonsteroidal agonist enobosarm (negative control), and the SARD 11)interact with AF-1 and/or alter the folding of this domain the steadystate fluorescence was measured for each compound with AR-AF1 alone orthe presence of TMAO (3 M) or the denaturant urea (4 or 6 M). 1 μM ofAR-AF1 and 5 μM of the individual compounds were used, and preincubatedfor at least 30 minutes prior to measuring the emission spectra. Theemission spectra were all corrected for buffer alone or buffer withTMAO/urea/compounds as necessary. FIG. 17A-C presents biophysical datathat suggests that SARDs bind to the N-terminal domain of the AR (inaddition to the LBD in the C-terminus reported as K_(i) values herein).FIG. 17A: Dose-dependent shift in the fluorescence intensity by 11 whenincubated with AR AF-1. The fluorescence shoulder observed at 307 nm,which corresponds to tyrosine residues in the AF-1, is shifted by 11.FIG. 17B: The overall fluorescence is also markedly altered byincreasing concentrations of 11. FIG. 17C: Data shown in FIG. 17A wasplotted as a difference in fluorescence between control and 11 treatedsamples (fluorescence in the absence of compound—fluorescence in thepresence of compound), a dose dependent increase was observed in thepresence of 11, consistent with binding to and stabilization of theintrinsically disordered AR-AF1 peptide derived from the NTD of AR. Thisdata demonstrated binding of SARDs to the NTD domain. Only EPI-001 isreported to bind NTD but is not orally bioavailable. Enzalutamide andARN-509 bind to the LBD only. This demonstrates the uniqueness of thecompounds of this invention that are highly potent and selectiveandrogen receptor degraders of a variety of full-length andsplice-variant androgen receptors (Examples 5-8 and 13), potentinhibitors of LBD-dependent transactivation (Examples 5-8, 10, and 13),and inhibit NTD-dependent activity (Example 9) via binding to the NTD(Example 12). Based on their unique profile of AR antagonisticmechanisms, there is great expectation to expand the scope of diseasestreatable with the androgen receptor antagonist compounds of thisinvention reported herein.

Based on half-maximum saturation for the change in fluorescence signal(at λmax 242 nm), the binding constant to AR-AF1 was calculated to be ofKD=1.34±0.32 μM (n=3, mean±SEM).

1 μM AR-AF1 was pre-incubated without or with increasing concentrationsof compound 11 (up to 15 μM) and steady-state fluorescence emission,after excitation at 287 nm, measured from 300 to 400 nm. Data wasanalysed as described by Epps et al (1999) J. Pharm 51, 41-48, Rawel etal (2006) Mol. Nutr. Food Res. 50, 705-713 and Wang et al (2011) Mol.Endcor. 25, 2041-2053 which are hereby incorporated by reference.

Surface Plasmon Resonance (SPR): To confirm the results obtained by FPassay, a biotin labeled method using AF-1 was employed. Biacore assayuses surface plasmon resonance (SPR) to measure protein-proteininteraction and protein-small molecule interaction. In this assay, ARAF-1 and 50 nM of 11 were added to a Biacore chip and SPR was measured.11 demonstrated a change in the refraction index in the SPR, indicatingan interaction with the AR AF-1 protein (FIG. 47 ).

NMR studies confirm the binding of 11 to AF-1 between amino acids244-360. ¹H NMR is consistently used in high-throughput screens todetect the binding of small molecules less than 500 Da to large proteinsgreater than 5 KDa [Dias, D. M., and Ciulli, A. (2014). NMR approachesin structure-based lead discovery: recent developments and new frontiersfor targeting multi-protein complexes. Prog Biophys Mol Biol 116,101-112; Shortridge, M. D., Hage, D. S., Harbison, G. S., and Powers, R.(2008). Estimating protein-ligand binding affinity using high-throughputscreening by NMR. J Comb Chem 10, 948-958.]. It is easier to useone-dimensional (1D) NMR to observe changes in line-width or linebroadening as a high-throughput method to identify the binding of themolecules to proteins and then use two-dimensional (2D) NOE-based NMRtechniques such as Water ligand-observed spectroscopy (WaterLOGSY) asconfirmatory methodology [Dalvit, C., Pevarello, P., Tato, M., Veronesi,M., Vulpetti, A., and Sundstrom, M. (2000). Identification of compoundswith binding affinity to proteins via magnetization transfer from bulkwater. J Biomol NMR 18, 65-68; Shortridge et al., 2008].

All these experiments are based on the fact that NMR observables such aslinewidths and NOE's vary dramatically between small molecules and heavymolecules. The decreased rotational correlation times upon binding of asmall molecule ligand to a heavy target molecule produce an atypicalheavy molecule NMR result characterized by broadened and weaker ofligand peaks in 1D NMR and negative NOE peaks in the waterLOGSY ascompared to the free state. In the absence of any affinity, the smallmolecule NMR result is obtained (sharp peaks in 1D NMR and positiveNOE's). This distinction provides the basis for NMR screeningexperiments.

Using these principles ¹H NMR was used to confirm the binding of 11 toAF-1 protein. In the first experiment, 11 or enzalutamide (500 μM) wasdissolved in deuterated DMSO (DMSO-d₆) and was incubated alone or mixedwith 5 μM GST-AF-1 or GST and the binding of the molecules to theprotein was determined by NMR. While 11 alone or in combination with GSTexhibited sharp peaks revealing that the ligand was present in the freestate, 11 in combination with GST-AF-1 provided a broadened and weakerpeaks (FIG. 46A; peaks in box) revealing that 11 has affinity for theAF-1 protein. Enzalutamide is a traditional AR antagonist known tocompetitively bind to the LBD. No line broadening was observed uponaddition of enzalutamide to AF-1 revealing no affinity for AF-1. Thisresult confirms that the 11, but not enzalutamide, binds to the AF-1domain. To further confirm the 1D NMR results, we performed WaterLOGSYwith 11 alone or in combination with AF-1. While the 11 alone gave aflat signal, i.e., no negative NOE's as expected for a free state smallmolecule, 11 in combination with AF-1 provided a negative signalcharacteristic of binding to the protein (FIG. 46B).

To determine precisely the region where 11 binds to the AF-1 region(since the AF-1 region is between 141 and 486 amino acids), we createdsmaller fragments of the AF-1 gene and purified the proteins coded forby fragments (FIG. 46C). 11 was incubated alone or in combination withGST, GST-AF-1 or with various fragments of the AF-1 region and 1D ¹H NMRprofile was obtained. Similar to the results shown in FIG. 46A, 11provided a sharp signal by itself and when co-incubated with GST, butline broadening when incubated with the AF-1 (FIG. 46D). Similar to theunbound ligand, 11 in combination with fragments 1A and 5T producedspectra suggestive of free state. However, when 11 was incubated withfragment 1T, the signal was almost indistinguishable from line,indicating a strong binding affinity to this region. The profile of 11in combination with 1B looked similar to that of the AF-1, confirmingthe binding to this region. Binding of 11 to 1T and 1B, but not to 1A,indicates that amino acids 51-211 could be excluded and that potentiallythe binding occurs between amino acids 244 and 360.

Three separate biophysical phenomena, FP, SPR, and NMR indicate that 11and other SARDs of this invention have significant affinity for AF-1,suggestive of binding strong enough to mediate some of the uniquecharacteristics of the AR antagonists reported herein.

Example 13

Androgen Receptor Binding and Transactivation of Carbazole Based SARDsLigand Binding Assay

Objective: To determine SARDs binding affinity to the AR-LBD.

Method: hAR-LBD (633-919) was cloned into pGex4t.1. Large scaleGST-tagged AR-LBD was prepared and purified using a GST column.Recombinant ARLBD was combined with [³H]mibolerone (PerkinElmer,Waltham, Mass.) in buffer A (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA,0.25 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determine theequilibrium dissociation constant (K_(d)) of [³H]mibolerone. Protein wasincubated with increasing concentrations of [³H]mibolerone with andwithout a high concentration of unlabeled mibolerone at 4° C. for 18 hin order to determine total and non-specific binding. Non-specificbinding was then subtracted from total binding to determine specificbinding and non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻² M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BioGel HT® hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i) (Table 12).

Transactivation Assay for Wt and Mutant AR

Objective: To determine the effect of SARDs on androgen-inducedtransactivation of AR wildtype (wt) or AR carrying known AR-LB mutants(i.e., W741L or T877A).

Method: HEK-293 cells were plated at 125,000 cells/well of a 24 wellplate in DME+5% csFBS without phenol red. Cells were transfected with0.25 ug GRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) orCMV-hAR(W741L) or CMV-hAR(T877A) using Lipofectamine transfectionreagent in optiMEM medium. Medium was changed 24 h after transfection toDME+5% csFBS without phenol red and treated with a dose response ofvarious drugs (Table 12: compounds 200-205) (1 pM to 10 □M). SARDs andantagonists were treated in combination with 0.1 nM R1881. Luciferaseassay was performed 24 h after treatment on a Biotek synergy 4 platereader. Firefly luciferase values were normalized to renilla luciferasevalues.

Transactivation Assay: wt and Mutant ARObjective:

To determine the effect of SARDs on androgen-induced transactivation ofAR carrying known AR-LBD mutants.

Method: HEK-293 cells were plated at 125,000 cells/well of a 24 wellplate in DME+5% csFBS without phenol red. Cells were transfected with0.25 ug GRE-LUC, 10 ng CMV-renilla LUC, and 50 ngCMV-hAR/W741L-AR/T877A-AR using Lipofectamine transfection reagent inoptiMEM medium. Medium was changed 24 h after transfection to DME+5%csFBS without phenol red and treated with a dose response of variousdrugs (1 pM to 10 □M). SARDs and antagonists were treated in combinationwith 0.1 nM R1881. Luciferase assay was performed 24 h after treatmenton a Biotek synergy 4 plate reader. Firefly luciferase values werenormalized to renilla luciferase values. (Table 12)

AR Degradation was Performed Using LNCaP, 22RV1, and AD1 Cells asDescribed Herein Above and in Example 13.

Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds:

Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage of −4200 V (negative mode).Declustering potential, entrance potential, collision energy, production mass, and cell exit potential were optimized for each compound.

TABLE 12 AR Binding, Inhibition of wt and mutant AR Transactivation, ARdegradation and in vitro metabolic stability of SARDs. TranscriptionalActivation (+0.1 nM R1881; R1881 EC₅₀ = 0.11 nM T_(1/2) (min) BindingWt. W741L T877A CL_(int) Compound K_(i) (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀(nM) (μl/min/mg) DHT 1 — — — R-Bicalutamide 545.5 248.2 — 557Enzalutamide 205.2 216.3 939 331.94 ARN-509 — 297.0 1939.41 390.50(apalutamide) ASC-J9 — 1008.0 3487.68 2288.16 200 728.59 871.21 41.77min 16.6 μl/min/mg 201 506.94 237.91 89.68 min 7.729 μl/min/mg 202

The relatively long half-lives (T_(1/2)) and low metabolic clearance(CL_(int)) values in vitro for compounds 200-202 of this inventionsuggest the possibility of oral bioavailability and stability in serumwhich would be favorable for systemic treatment of diseases of thisinvention such as prostate cancer, breast cancer, Kennedy's disease, andvarious androgen-dependent diseases. Similarly, indazoles such as 96also demonstrated enhanced stability, as discussed herein above.

TABLE 13 AR Binding (Ki), Inhibition of AR Transactivation (IC50), ARDegradation and in vitro Metabolic Stability of SARDs. DMPKBinding/Transactivation SARD Activity (MLM) Log P (wt AR) Full LengthS.V. (22RV1) T_(1/2) (min) (−0.4 to K_(i) (nM) % inhibition % inhibitionCL_(int) (μl/ Compd ID Structure +5.6) (DHT = 1 nM) IC₅₀ (nM) at 1.10 μMat 10 μM min/mg) Enobosarm

3.44  20.21 ~20  R-Bicalutamide

2.57  508.84 248.2 Enzalutamide

4.56 3641.29 216.3 ARN-509 (apalutamide)

3.47 1452.29 0   (FIG. 26)  0

2.57  87.67 —

1.86  407.08 200

4.36  728.59  871.21 48   (FIGS. 26, 27) 60 41.77 16.6  201

4.40  506.94  237.91 33   (FIGS. 27, 28) 89.68  7.729 202

4.52  193.80  991.15 20   29 39.94 17.35 203

4.16  248.54 1242.96 38    0 204

4.68  809.64 See FIG. 29N 1025.41 See FIG. 29N 51   205

4.00  90.68 See FIG. 29L 1079.11 See FIG. 29L 19.87 See FIG. 29L 87 SeeFIG. 29L

TABLE 14 Liver Microsome (LM) Data for Carbazoles of this Inventionusing Mouse LM (MLM), Human LM (HLM), Rat LM (RLM), and Dog LM (DLM).MLM HLM RLM DLM T_(1/2) CL_(int) T_(1/2) CL_(int) T_(1/2) CL_(int)T_(1/2) CL_(int) Compd ID (min) (μl/min/mg) (min) (μl/min/mg) (min)(μl/min/mg) (min) (μl/min/mg) 200 95.9 0.72 (5-carbazole) 201 89.687.729 61.38 0.01129 202 39.94 17.35 14.28 48.54

Example 14

AR Degradation Using Compounds of this Invention

LNCaP Degradation Assay

Objective: To determine the effect of SARDs on AR expression in LNCaPcells.

Plasmid constructs and transient transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC50 obtained from four parameter logistics curve.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BioGel HT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

LNCaP Gene Expression Assay.

Method: LNCaP cells were plated at 15,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Forty-eight hours after plating,cells were treated with a dose response of SARDs. Twenty four hoursafter treatment, RNA was isolated using cells-to-ct reagent, cDNAsynthesized, and expression of various genes was measured by realtimertPCR (ABI 7900) using taqman primers and probes. Gene expressionresults were normalized to GAPDH.

LNCaP Growth Assay.

Method: LNCaP cells were plated at 10,000 cells/well of a 96 well platein RPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method: LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 μM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method: 22RV1 and D567es cells expressing AR splice variants were platedat 750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 Growth and Gene Expression.

Methods: Cell growth was evaluated as described before by SRB assay.Cells were plated in 96 well plate in full serum and treated for 6 dayswith medium change after day 3. Gene expression studies were performedin 22RV1 cells plated in 96 well plate at 10,000 cells/well in RPMI+10%FBS. Twenty four hours after plating, cells were treated for 3 days andgene expression studies were performed as described before.

Results:

FIG. 26 presents AR degradation by 200 vs. ARN-509 in LNCaP cells.Western blot analysis by the method described above demonstrated theability of 200 to degrade a mutant AR (i.e., T877A) at 100 nM and 10 μMin LNCaP cells whereas ARN-509 only degraded at 10 μM, suggesting thatSARDs such as 200 will have clinical utility in prostate cancersincluding those whose growth is driven by antiandrogenresistance-conferring mutant AR's (i.e., advanced prostate cancers andCRPC).

FIG. 27 and FIG. 28 present AR and AR-V7 degradation by 200 and 201 in22RV-1 cells. 200 was capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-V7) in 22RV-1 cells, suggesting that SARDsmay be able to overcome AR-V7 dependent prostate cancers (i.e., CRPC).By comparison, 201 demonstrated low levels of degradation in 22RV-1cells.

These SARD activity demonstrations in FIGS. 26-28 as well as reported inthe Tables suggest the compounds of this invention are able to degrade avariety of AR variants, and hence should provide the ability to inhibitthe AR-axis activity whether it is androgen-dependent orandrogen-independent. Degradation of the AR removes the possibility ofpromiscuous activation of mutant ARs, activation by intracellularprocesses such as signal transduction and kinase activation, etc.; andsuggests that the SARDs should also degrade the polyQ polymorphism inhyperandrogenic dermatologic disorders (shortened polyQ) or Kennedy'sdisease (extended polyQ), providing a rationale for treating either typeof diseases by destroying the AR in the affected tissues (skin andneuromuscular system, respectively).

Example 15

Further studies with SARDs

PCa Gene Expression and Cell Growth:

PCa cells (LNCaP and 22RV1) will be plated at 10,000 cells per well of a96 well plate in respective medium supplemented with 1% csFBS or in fullserum. The cells will be maintained for 3 days and will be treated withSARDs or controls alone or in combination with 0.1 nM R1881 (1% csFBS).RNA will be isolated and cDNA prepared using cells-to-ct kits (LifeTechnologies). Expression of various androgen-regulated genes will bemeasured using TaqMan primer probe mix on an ABI 7900 realtime PCRmachine. The expression of individual genes will be normalized to 18SrRNA levels.

PCa cells will be plated at 10,000 cells per well of a 96 well plate inrespective medium supplemented with 1% csFBS or in full serum. The cellswill be treated with SARDs alone or in combination with 0.1 nM R1881.The cell viability will be measured using Sulforhodamine blue reagent.As negative control, AR-negative PC3 cells will be treated similarly toensure the absence of any non-specific growth inhibitory properties ofSARDs.

Preclinical Rodent Pharmacokinetic (PK) Studies:

The PK parameters of SARDs in various formulations will be determined inrats and mice as appropriate. Approximately 250 gram Sprague-Dawley ratswill be randomized into groups of 5 and a catheter surgically implantedinto the jugular vein. After a recovery period the rats will beadministered test compound and 250 μL of venous blood will be seriallysampled from the catheter at 0, 10, 20, 30, 60, 120, 240, 480, 720, 1440and 2880 minutes post administration for an intravenous dose or 0, 20,40, 60, 90, 120, 150, 180, 210, 240, 480, 720, 1440, and 2880 minutespost administration for a non-intravenous dose. For mice, approximately20 gram C57BL/6 mice will be grouped into three per time point per routeof administration. Following administration of an intravenous dose micewill be sacrificed and blood collected by cardiac puncture at 0, 10, 20,30, 60, 120, 240, 480, 720, 1440 and 2880 minutes after intravenousdosing or 0, 30, 60, 90, 120, 150, 180, 210, 240, 480, 720, 1440, 2880minutes after dosing for a non-intravenous dose. Samples will becollected in appropriate anti-coagulant containing tubes and plasmaprepared for LC-MS-MS analyses. Relevant PK parameters will be estimatedvia non-compartmental analyses using Phoenix WinNonlin.

PCa Xenograft Studies:

Nod Scid γ (NSG)/nude mice (6-8 weeks in age) will be used in thexenograft experiments. Briefly, a mixture of 1:1 LNCaP or 22RV-1 cellsin medium (10% FBS supplemented medium):matrigel mixture will beimplanted subcutaneously in male NSG mice. Cell number to be implantedwill depend on the cell type. Tumors will be implanted in male nude micethat have high circulating androgens or in castrated animalssupplemented with DHT to streamline the hormone circulation and toreduce variability between animals. For CRPC model, animals will becastrated when VCaP tumors reach 100 mm³ and the tumors will be allowedto re-grow as CRPC. Animals will be randomized into groups once thetumors reach 200 mm³ and will be treated daily with vehicle orrespective SARD. Tumor volume will be measured thrice weekly and theanimals will be sacrificed at the end of the study. At sacrifice, tumorswill be weighed and stored for further histological and molecularbiological analysis. Tumor volume will be calculated using the formulalength×width×width×0.5236. Cai et al. (Cancer Research, 71(20), 2011)have characterized VCaP cells as expressing high levels of androgenbiosynthesis enzymes CYP17A1, AKR1C3, and HSD6B resulting in highintratumoral androgen levels.

Example 16

In Vivo Studies of SARDs (indoles and indolines)

Hershberger assay: Mice (6-7 weeks old) were treated with vehicle orindicated SARDs (100 mg/kg/day twice daily) for 14 days orally. Animalswere sacrificed and seminal vesicles (S.V.) weights were recorded andrepresented.

Results: SARDs 11, 34, 36, 37, 38, 103, and 115 demonstrated varyinglevels of inhibition of seminal vesicles (S.V.) growth. 103 and 36 hadthe greatest effect on suppressing S.V. growth (FIGS. 30A and 30D),prostate (FIG. 30C), and also had an effect of body weight (FIG. 30B).This suggests that these SARDs, despite low levels in the serum, wereable to exert antiandrogenic effects on androgen dependent organs,supporting their potential use as treatments for prostate cancer andother diseases as described herein.

SARDs were also investigated in xenograft studies. 103 demonstrated lowlevels of efficacy in patient derived (FIG. 31 ) and mouse (FIG. 32 )xenografts despite very low levels in the plasma.

TABLE 15 SARDs are detected in plasma and patient derived tumor. Conc of103 (nM) Plasma Sample #768 3.81 Plasma Sample #769 18.4 Tumor Sample#768 142 Tumor Sample #769 282 Calibration Curve Range 1.95-2000 Nm R²0.9957 Regression Quadratic Weighting 1/x²

However, unexpectedly 103 was found to accumulate in the tumor (Table15), possibly explaining its activity in the xenografts.

SARDs selectively accumulate in tumor: NSG mice were implanted withpatient-derived prostate cancer xenograft. Animals were treated for 14days and tumor volumes were measured twice weekly. Animals weresacrificed, 103 extracted from serum and tumor and measured using aLC-MS/MS method.

103 selectively accumulates in tumor with almost 10 times more tumoraccumulation than in plasma. While 103 had weak activity in tumorxenografts, 36 demonstrated promising inhibition of tumor growth.

Example 17

SARDs Inhibit Transcriptional Activation of F876L

To validate that SARDs of the invention can antagonize the R1881-driventranscriptional activation of mutant AR F876L, COS cells weretransfected with F876L AR with a GRE-driven luciferase reporterconstruct, and a Renilla reporter construct as a control fortransfection efficiency. Cells were treated 24 h after transfection with0.1 nM R1881 (AR agonist) and a dose response of SARDs. Luciferase (andRenilla) assays were performed 48 h after transfection and reported asrelative light unit (RLU). COS is not a prostate cancer cell line, sotransfection with F876L does not confer enzalutamide resistance (Enz-R).FIG. 50A (top middle panel) demonstrated potent (low nM) but not fullefficacy antagonism by enzalutamide of R1881-driven F876L transactivation, whereas wt AR inhibition was less potent (low μM) and fullefficacy. Importantly, at high concentrations (>1 μM), enzalutamide actsas an agonist of F876L transactivation (top right panel of FIG. 50A),which is not seen in wt AR. This is indicative that F876L acts like anagonist switch escape mutant of enzalutamide therapy. Given that SARDsof this invention were structurally novel high potency AR antagonistswith a unique biological activity profile, representative compounds(i.e., 11 (5-F indole), 22 (4-F indole), 23 (6-F indole), 37 (5-Findole), 101 (4-F indoline), and 36 (4-F indole)) were tested for theirability to overcome the agonist switch behavior. Approximatelyequipotent nM range, full efficacy antagonism of R1881-driventranscriptional activation was observed in both F876L and wt. Thissuggested that SARDs of this invention would also exhibit activity inmodels of Enz-R (e.g., MR49F cells) and primary prostate cancer (PC)possessing wt AR.

Example 18

SARD Activity and Cellular Anti-Proliferation in the MR49F Model of ofEnzalutamide resistant prostate cancer (Enz-R PC)

To ensure that SARD activity was also maintained in a Enz-R cell line,SARD assays were performed in MR49F LNCaP cells containing theF876L/T877A double mutant. As seen in FIG. 50B, 36 (4-F indole) and 115(5-F, 6-Ph indoline) degraded this mutant FL AR in MR49F cells in thelow μM and high nM range, respectively, consistent with the relativeactivities seen in Tables 3 and 6. Densitometric evaluation of theimmunoblots suggests that 115 demonstrated similar to improved potencyof SARD activities in the Enz-R LNCaP (FIG. 50A) when compared to theparental enzalutamide sensitive LNCaP shown supra (FIG. 49A). Thissuggests that the optimized activity profile for 115 reported in Table 6was conserved in this model of Enz-R. Enzalutamide was inactive in SARDactivity assays in LNCaP (FL) and 22RV1 (SV) cells and was not tested inMR49F cells as it was not expected to be a SARD in this or any cellularcontext. The preservation of SARD activity for these representativecompounds even in the Enz-R context suggested that SARDs of theinvention may exhibit broad spectrum anti-proliferative and/oranti-tumor activities across many prostate cancers includingenzalutamide-resistant prostate cancers.

Anti-proliferative assays in MR49F cells showed that 103 (4-F indoline),36 (4-F indole), and 34 (5-F, 6-Ph indole) completely anddose-dependently inhibited cell growth with estimated IC₅₀ values ofless than 3 μM for 103 and 36, and less than 1 μM for 34 (FIG. 51 ). For36 at least, this correlates well with in vitro proliferative antagonismand SARD activity in MR49F cells (FIGS. 50A and 50B), suggesting thatSARDs of this invention retained their unique biological profile inEnz-R PC. By comparison, enzalutamide demonstrated weak and incompleteefficacy as revealed by poor dose-dependence and only partial inhibitionof growth. E.g., growth inhibitions at 3 μM, 10 μM and 30 μM wereapproximately 30%, 15% and 45%. This result demonstrated theenzalutamide resistant of these MR49F cells, and further affirmed ourability to overcome the Enz-R phenotype with representative examples ofSARDs of this invention, supporting testing in MR49F xenografts.

Example 19

In Vivo Antagonism

Hershberger assays. Hershberger assays were performed on several SARDsof this invention in intact mice and rats. Surprisingly, despite poormouse liver microsome (MLM) stabilities, the tested SARDs (103, 104, 23,34, 11, 36, 37, 38 and 115) caused atrophy of AR-dependent seminalvesicles tissue in intact mice (FIG. 52A, left panels) whereas vehicledid not have any effect (0% change). Similar efficacy atrophy was alsoobserved for 103 and 104 in rats (FIG. 52A, right panel) and wasdemonstrated to be dose-dependent in prostate and seminal vesicles, withup to ˜40% change in organ weights relative to castrated control (100%).This confirms that orally administered compounds are being absorbed anddistributed to the site of action in these organs and suggests that thecompound should also distribute to tumors in xenograft models to exertanti-tumor effects in sensitive models.

MR49F Xenografts in mice: MR49F xenografts were established byimplanting the Enz-R LNCaP cells (from University of British Columbia)mixed with Matrigel (BD Biosciences, San Jose, Calif.) at 1:1 ratio andinjecting subcutaneously in NOD SCID gamma (NSG) mice. Once tumor sizesreached 100-200 mm³, the mice were castrated and the tumors were allowedto regrow as CRPC. The animals were randomized once the tumors startedto regrow and treated with vehicle (polyethylene glycol-300: DMSO 85:15ratio) or 100 mg per kg of SARDs 34 or 36 for 14 d. In FIG. 52B, 34 and36 significantly reduced the tumor volume with a 40-60% tumor growthinhibition (TGI).

Further, the significant levels of TGI activity indicated that the oralbioavailability demonstrated in Hershberger assays translated toadequate levels of 34 and 36 in tumor to reveal to some extent thepharmacodynamic behavior of the SARDs of this invention. \Theproof-of-concept that the SARDs of the invention can overcome Enz-R CRPCin vivo was established through the susceptibility of these Enz-Rxenografts to 34 and 36. This promising result is surprising given thepoor metabolic stability of these SARDs as a whole in the same species(mice) as seen in MLM (Tables 4 and 6; T1/2 for 34 and 36 were 9.13 minand 11.77 min). These experiments indicate that the SARDs of thisinvention with their unique biological profile could be used to overcomeenzalutamide, and by extension apalutamide and abiraterone, resistances,in CRPC patients.

SARD compounds of the invention as described herein are potent ARantagonists and with a broad activity profile in models of prostatecancer, and in vivo AR antagonism when orally administered. For example,SARDs exhibited strong AR antagonistic activity in vitro intranscriptional activation and cellular proliferative assays includingin models of enzalutamide sensitive and resistant PCs, and/or castrationresistant PCs (CRPCs).

Additionally, SARDs of the invention showed selective AR [protein]degradation of full-length (FL AR; e.g., from LNCaP cells (T877A)) andsplice variant (SV AR; e.g., from 22RV1 cells (AR-V7)) isoforms of AR,all at sub to low micromolar treatment levels, and in a variety ofprostate cancer cell contexts including enzalutamide resistant PCs(e.g., MR49F). The ability to degrade SV AR in the study suggested thepotential of SARDs of this invention to treat various currentlyuntreatable advanced and refractory PCs, for example, those lacking theligand binding domain (LBD) of AR such as AR-V7 and D567es ARtruncations, which are not susceptible to androgen-deprivation therapy,abiraterone, or LBD-directed antiandrogens (e.g., enzalutamide,apalutamide, and bicalutamide), and are associated with short survival.

Further, in vivo investigation found that the SARDs of the inventionovercome a variety of escape mutants including F876L and F876L/T877A(MR49F) that are known to emerge due to enzalutamide treatment. Thesemutations convert enzalutamide and apalutamide to agonists, conferringresistance to prostate cancer cells and tumors via an agonist switchmechanism as seen with other LBD-binding antiandrogens, e.g. W741L forbicalutamide and T877A for flutamide(N-(4-nitro-3-(trifluoromethyl)phenyl)isobutyramide). The intractabilityof truncation mutants and the frequency of the agonist switch mutationssuggest that novel ways, potentially LBD-independent ways, of targetingthe AR are needed. Moreover, these orally bioavailable SARDs are dualacting agents, i.e., potent inhibitors and degraders of AR, providing ahigher evolutionary barrier to the development of resistance to SARDs.N-terminally directed SARDs such as the SARDs of this invention mayprovide a next generation of AR antagonists to treat a variety ofrefractory and/or advanced prostate cancers, includingenzalutamide-resistant, castration resistant, and/or AR-V7 dependent PCswhich are not amendable with current hormone therapies. As such, SARDsmay delay the need to rely solely on chemotherapy.

SARDs of the invention have a unique biological activity profileoptimized to address Enz-R CPRC, including:

1) Generally bind to LBD of AR;2) Inhibit transcriptional activation of wildtype AR, escape mutant ARs(T877A in Tables 3 and 6, F876L in FIG. 50A, and Q711A3) Exert high efficacy and potency SARD activity against FL and SV ARwhether wildtype or harboring point-mutations (LNCaP in Tables 3 and 6)or truncations (22RV1 in Tables 3 and 6), including an Enz-R cellularcontexts (e.g., MR49F in FIG. 50B);4) Exert AR antagonism in vivo when administered orally in intactanimals (FIG. 52A);5) Exert PC anti-proliferative activity in vitro (FIG. 51 ) and in vivo(see LNCaP, 22RV1) including in Enz-R CRPC (FIG. 52B); and6) Bind to a secondary binding site in AF-1 believed to mediate SARDactivity as demonstrated for 11 by steady fluorescence and NMR studies,as demonstrated herein.

Example 20

SBMA Method

Transgenic mice that express AR121Q (121 polyglutamine repeats insteadof the usual 15-24 repeats) will be treated with vehicle or SARD orally.One group of mice will be castrated to serve as positive control ascirculating androgens will worsen the SBMA (X-linked spinal-bulbarmuscular atrophy) condition. Body weight, composition, and grip strengthwill be measured before the initiation of the experiment. Animals willbe treated and weekly measurements will be performed. Animals will betreated and monitored until they die. AR121Q mice live only up to 60-80days and hence evaluating the survival in the presence of SARD treatmentis possible.

ALS Method

All experiments will be performed in male hSOD1-G93A mice (Jax labs;PMID: 26786249) as a model of anterior lateral sclerosis (ALS). Micewill be randomized and treated with either vehicle or SARD of thisinvention dissolved in DMSO+PEG-300 (15%+85%). Simultaneously, a groupof mice will be castrated and used as positive control as castration hasbeen shown to extend survival and disease duration in this model (PMID:24630363). Mice will be treated orally every day until they reachmorbidity. Weekly body weight and composition by magnetic resonanceimaging (MRI) will be recorded. The mice performance will be measuredeach week by using a grip strength meter (Columbus instruments) orrotarod. Inability for the mice to move will be considered as a terminaldisease state and the mice will be sacrificed.

Example 21 Synthesis of Benzotriazole SARD Compounds(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)propanamide(C₁₉H₁₃F₆N₅O₂)(300)

To a solution of 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (0.20 g,0.0010688 mol) in anhydrous THF (5 mL), which was cooled in an ice waterbath under an argon atmosphere, was added sodium hydride (60% dispersionin oil, 0.13 g, 0.0033134 mol). After addition, the resulting mixturewas stirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.375 g, 0.0010688 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (9:1) as eluent to afford0.044 g (9%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.40 (s, 1H, ArH), 8.38(s, 1H, ArH), 8.23 (d, J=8.4 Hz, 1H, ArH), 8.11 (d, J=8.4 Hz, 2H, ArH),7.67 (d, J=8.6 Hz, 1H, ArH), 6.67 (s, 1H, OH), 5.24 (d, J=14.0 Hz, 1H,CH), 4.99 (d, J=14.0 Hz, 1H, CH), 1.55 (s, 3H, CH₃).

Mass (ESI, Negative): 456.25 [M−H]⁻; (ESI, Positive): 458.10[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)propanamide(C₁₉H₁₃F₆N₅O₂) (301)

To a solution of 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (0.20 g,0.0010688 mol) in anhydrous THF (5 mL), which was cooled in an ice waterbath under an argon atmosphere, was added sodium hydride (60% dispersionin oil, 0.13 g, 0.0033134 mol). After addition, the resulting mixturewas stirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.375 g, 0.0010688 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (3:1 to 2:1) as eluentto afford 0.025 g (5%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H, NH), 8.39 (d, J=1.6 Hz, 1H,ArH), 8.33 (s, 1H, ArH), 8.25 (d, J=8.8 Hz, 1H, ArH), 8.12 (dd, J=8.8Hz, J=2.0 Hz, 1H, ArH), 8.07 (d, J=8.4 Hz, 1H, ArH), 7.64 (dd, J=8.8 Hz,J=1.6 Hz, 1H, ArH), 6.64 (s, 1H, OH), 5.21 (d, J=14.4 Hz, 1H, CH), 5.01(d, J=14.4 Hz, 1H, CH), 1.54 (s, 3H, CH₃).

Mass (ESI, Negative): 456.25 [M−H]⁻; (ESI, Positive): 458.10[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)propanamide(C₁₉H₁₃F₆N₅O₂) 302

To a solution of 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (0.20 g,0.0010688 mol) in anhydrous THF (5 mL), which was cooled in an ice waterbath under an argon atmosphere, was added sodium hydride (60% dispersionin oil, 0.13 g, 0.0033134 mol). After addition, the resulting mixturewas stirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.375 g, 0.0010688 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (3:1 to 2:1) as eluentto afford 0.023 g (5%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H, NH), 8.50 (s, 1H, ArH), 8.34(d, J=1.6 Hz, 1H, ArH), 8.18 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d,J=8.8 Hz, 1H, ArH), 8.08 (d, J=8.4 Hz, 1H, ArH), 7.84 (dd, J=8.8 Hz,J=1.6 Hz, 1H, ArH), 6.49 (s, 1H, OH), 5.15 (d, J=14.4 Hz, 1H, CH), 4.97(d, J=14.4 Hz, 1H, CH), 1.52 (s, 3H, CH₃).

Mass (ESI, Negative): 456.25 [M−H]⁻; (ESI, Positive): 458.10[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-fluoro-2H-benzo[d][1,2,3]-triazol-2-yl)propanamide(C₁₈H₁₃F₄N₅O₂) (303)

To a solution of 5-fluoro-1H-benzo[d][1,2,3]triazole (0.20 g, 0.001459mol) in anhydrous THF (5 mL), which was cooled in an ice water bathunder an argon atmosphere, was added sodium hydride (60% dispersion inoil, 0.18 g, 0.004522 mol). After addition, the resulting mixture wasstirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.51 g, 0.001459 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (3:1 to 2:1) as eluentto afford 0.115 g (19.4%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H, NH), 8.43 (s, 1H, ArH), 8.32(d, J=8.2 Hz, 1H, ArH), 8.11 (d, J=8.2 Hz, 1H, ArH), 7.95-7.91 (m, 1H,ArH), 7.67 (d, J=8.8 Hz, 1H, ArH), 7.33-6-7.31 (m, 1H, ArH), 6.53 (s,1H, OH), 5.14 (d, J=13.6 Hz, 1H, CH), 4.90 (d, J=13.6 Hz, 1H, CH), 1.53(s, 3H, CH₃).

Mass (ESI, Positive): 430.09 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)propanamide(C₁₈H¹³F⁴N₅O₂) (304)

To a solution of 5-fluoro-1H-benzo[d][1,2,3]triazole (0.20 g, 0.001459mol) in anhydrous THF (5 mL), which was cooled in an ice water bathunder an argon atmosphere, was added sodium hydride (60% dispersion inoil, 0.18 g, 0.004522 mol). After addition, the resulting mixture wasstirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.51 g, 0.001459 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (3:1 to 2:1) as eluentto afford 0.075 g (12.6%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H, NH), 8.40 (s, 1H, ArH), 8.19(d, J=8.4 Hz, 1H, ArH), 8.10 (d, J=8.0 Hz, 1H, ArH), 8.07-8.04 (m, 1H,ArH), 7.70 (d, J=8.2 Hz, 1H, ArH), 7.28-6-7.23 (m, 1H, ArH), 6.45 (s,1H, OH), 5.05 (d, J=14.4 Hz, 1H, CH), 4.87 (d, J=14.4 Hz, 1H, CH), 1.50(s, 3H, CH₃).

Mass (ESI, Positive): 430.09 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)propanamide(C₁₈H₁₃F₄N₅O₂) (305)

To a solution of 5-fluoro-1H-benzo[d][1,2,3]triazole (0.20 g, 0.001459mol) in anhydrous THF (5 mL), which was cooled in an ice water bathunder an argon atmosphere, was added sodium hydride (60% dispersion inoil, 0.18 g, 0.004522 mol). After addition, the resulting mixture wasstirred for three hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.51 g, 0.001459 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (3:1 to 2:1) as eluentto afford 0.052 g (8.8%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H, NH), 8.38 (s, 1H, ArH), 8.20(d, J=8.8 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.92-7.89 (m, 1H,ArH), 7.84 (d, J=8.8 Hz, 1H, ArH), 7.46-7.42 (m, 1H, ArH), 6.46 (s, 1H,OH), 5.08 (d, J=14.4 Hz, 1H, CH), 4.90 (d, J=14.4 Hz, 1H, CH), 1.49 (s,3H, CH₃).

Mass (ESI, Positive): 430.09 [M+Na]⁺.

(S)-3-(5-Bromo-1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(306)

To a dry, nitrogen-purged 100 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (260 mg, 6.5 mmol) was added in 30 mL of anhydrous THF solvent inthe flask at ice-water bath, and 6-bromo-1H-benzo[d][1,2,3]triazole (514mg, 2.6 mmol) was stirred in over 30 min at the ice-water bath. Into theflask, the solution of(R)-3-bromo-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide(911 mg, 2.6 mmol) in 5 mL of anhydrous THF was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H₂O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, evaporated, dried overanhydrous MgSO₄, and evaporated to dryness. The mixture was purifiedwith flash column chromatography as an eluent EtOAc/hexane=1/2 toproduce designed compounds (Yield=65%: 42% for 306 and 23% of 307) asyellowish solid.

(S)-3-(5-Bromo-1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(306)

MS (ESI) m/z 467.81 [M−H]⁻; 492.00 [M+Na]⁺;

¹H NMR (400 MHz, CDCl₃) δ 9.10 (bs, 1H, NH), 8.04 (s, 1H), 8.02 (s, 1H),7.90 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H),7.49 (d, J=8.8 Hz, 1H), 5.48 (s, 1H, OH), 5.26 (d, J=13.6 Hz, 1H), 4.94(d, J=13.6 Hz, 1H), 1.54 (s, 3H);

¹⁹F NMR (CDCl₃, decoupled) δ−62.19.

(S)-3-(5-Bromo-2H-benzo[d][1,2,3]triazol-2-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(307))

MS (ESI) m/z 467.84 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 8.97 (bs, 1H, NH), 8.15 (s, 1H), 7.92 (s, 1H),7.75 (m, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 5.16 (d,J=14.2 Hz, 1H), 4.79 (s, 1H, OH), 4.78 (d, J=14.2 Hz, 1H), 1.65 (s, 3H);

¹⁹F NMR (CDCl₃, decoupled) δ−62.26.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-(4-fluorophenyl)-1H-benzo[d][1,2,3]triazol-1-yl)-2-hydroxy-2-methylpropanamide(308)

A mixture of 306 (150 mg, 0.32 mmol),tetrakis(triphenylphosphine)palladium (0) (13 mg, 12 mmol) andtrimethoxyboric acid (50 mg, 0.35 mmol) in THF/MeOH(1/1 mL) with sodiumcarbonate (82 mg, 7.69 mmol) in ethanol/water (5 mL/1 mL) were heated toreflux overnight. The mixture was cooled down to be concentrated underreduced pressure and poured into EtOAc, which was washed with water anddried over MgSO₄, concentrated, purified by silica gel chromatography(EtOAc/n-hexane=2:3) to afford 308 as a yellow solid.

Yield=90%;

MS (ESI) m/z 482.25 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.12 (bs, 1H, NH), 8.02 (s, 1H), 7.96 (s, 1H),7.92 (d, J=9.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H),7.59 (dd, J=7.6, 5.2 Hz, 2H), 7.17 (t, J=8.4 Hz, 2H), 5.72 (s, 1H, OH),5.28 (d, J=14.0 Hz, 1H), 4.97 (d, J=14.0 Hz, 1H), 1.55 (s, 3H); ¹⁹F NMR(CDCl₃, decoupled) δ−62.20, −114.49.

1-68. (canceled)
 69. A method of lowering prostate specific antigen(PSA) in a subject suffering from prostate cancer, comprisingadministering to the subject a therapeutically effective amount of aselective androgen receptor degrader (SARD) compound represented by thestructure of formula I:

wherein W₁ and W₂ are each independently selected from N; W₃, W₄, W₅ andW₆ are each independently selected from CH or N; wherein if any one ofW₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H is optionally replaced withR₄, Q or R₃ in the respective position, and if any one of W₁, W₂, W₃,W₄, W₅, and W₆ is not CH, then the respective position is unsubstituted;T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₄ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; n is an integer between 1, 2, or 3; and m is an integerbetween 1, 2, or 3; or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.70. The method of claim 69, wherein said compound is a compound offormula I(1):


71. The method of claim 69, wherein said compound is a compound offormula I(2):


72. The method of claim 69, wherein W₁, W₂, W₃, W₄, W₅, and W₆ are CH.73. The method of claim 69, wherein W₂ is N and W₁, W₃, W₄, W₅, and W₆are CH.
 74. The method of claim 69, wherein W₃ is N and W₁, W₂, W₄, W₅,and W₆ are CH.
 75. The method of claim 69, wherein W₁ is N and W₂, W₃,W₄, W₅, W₆ are CH.
 76. The method of claim 69, represented by thestructure of formula III:


77. The method of claim 69, wherein Q is H, NO₂, COR, alkyl, alkoxy,aryl, CN, CF₃, F, Cl, Br or I.
 78. The method of claim 69, wherein Z isCN.
 79. The method of claim 69, wherein Y is Cl or CF₃.
 80. The methodof claim 1, represented by the structure of the following compounds:


81. A method of treating testicular cancer, uterine cancer, ovariancancer, urogenital cancer, brain cancer, skin cancer, lymphoma, livercancer, renal cancer, osteosarcoma, pancreatic cancer, endometrialcancer, lung cancer, non-small cell lung cancer, gastric cancer, coloncancer, perianal adenoma, or central nervous system cancer to a subjectin need, comprising: administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound represented by the structure of formula I:

wherein W₁ and W₂ are each independently selected from N; W₃, W₄, W₅ andW₆ are each independently selected from CH or N; wherein if any one ofW₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H is optionally replaced withR₄, Q or R₃ in the respective position, and if any one of W₁, W₂, W₃,W₄, W₅, and W₆ is not CH, then the respective position is unsubstituted;T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₄ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; n is an integer between 1, 2, or 3; and m is an integerbetween 1, 2, or 3; or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.82. The method of claim 81, wherein said compound is a compound offormula I(1):


83. The method of claim 81, wherein said compound is a compound offormula I(2):


84. The method of claim 81, represented by the structure of formula III:


85. A method of treating multilocular uterus syndrome to a subject inneed, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound represented by the structure of formula I:

wherein W₁ and W₂ are each independently selected from N; W₃, W₄, W₅ andW₆ are each independently selected from CH or N; wherein if any one ofW₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H is optionally replaced withR₄, Q or R₃ in the respective position, and if any one of W₁, W₂, W₃,W₄, W₅, and W₆ is not CH, then the respective position is unsubstituted;T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₄ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; n is an integer between 1, 2, or 3; and m is an integerbetween 1, 2, or 3; or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.86. The method of claim 85, wherein said compound is a compound offormula I(1):


87. The method of claim 85, wherein said compound is a compound offormula I(2):


88. The method of claim 85, represented by the structure of formula III: